Organic compositions to treat kras-related diseases

ABSTRACT

The present disclosure relates to RNAi agents useful in methods of treating KRAS-related diseases such as a proliferative disease, including without limitation a solid or liquid cancer, adenocarcinoma, colorectal cancer, advanced and/or metastatic colorectal cancer, colon cancer, lung, non-small cell lung cancer and lung adenocarcinoma, acute myelogenous lung, bladder, brain, breast, cervical, endometrial, gastric, head and neck, kidney, leukemia, myelodysplastic syndrome, myeloid leukemia, liver, melanoma, ovarian, pancreatic, prostate, testicular, thyroid cancers, and cardio-facio-cutaneous (CFC) syndrome and Noonan syndrome, and similar and related diseases, using a therapeutically effective amount of a RNAi agent to KRAS.

BACKGROUND OF THE INVENTION

KRAS is a member of the RAS subfamily of small GTPases. It is involvedin cellular signal transduction, growth, differentiation, survival andother cellular functions. Over-expression or hyper-activity of KRAS,along with RAS family members HRAS and NRAS, have been associated with anumber of diseases, including various cancers. RAS mutations are foundin approximately one-third of all human malignancies. Bos et al. 1989.Cancer Res. 49: 4682-4689. KRAS accounts for most of the RAS mutationsfound in the majority of human malignancies, including 90% of RASmutations in lung adenocarcinomas. Forbes et al. 2006. Br. J. Cancer 94:318-322.

Mutations, hyper-activity and/or over-expression of KRAS in particularhas been associated with cancer, including adenocarcinoma, colorectalcancer (including advanced and metastatic colorectal cancer), coloncancer, lung (including non-small cell lung cancer and lungadenocarcinoma), acute myelogenous lung, bladder, brain, breast,cervical, endometrial, gastric, head and neck, kidney, leukemia,myelodysplastic syndrome, myeloid leukemia, liver, melanoma, ovarian,pancreatic, prostate, testicular, thyroid cancers, andcardio-facio-cutaneous (CFC) syndrome and Noonan syndrome, and similarand related diseases.

There exists the need for treatments related to KRAS-related diseases.

BRIEF SUMMARY OF THE INVENTION

The present disclosure encompasses RNAi (RNA interference) agents toKRAS, which are useful in the treatment of KRAS-related diseases, suchas cancer, cardio-facio-cutaneous (CFC) syndrome and Noonan syndrome,and similar and related diseases.

The present disclosure also encompasses a method of treating a humansubject having a pathological state mediated at least in part by KRASexpression, the method comprising the step of administering to thesubject a therapeutically effective amount of a RNAi agent KRAS.

The method also optionally further comprises the step of administering asecond agent. In some embodiments, this second agent is another RNAiagent to KRAS. In other embodiments, the second agent is anothertreatment, such as one directed to another target, which is alsohyper-active, mutated and/or over-expressed in the pathological state.

The present disclosure provides specific RNAi agents and methods thatare useful in reducing KRAS levels in a subject, e.g., a mammal, such asa human. The present disclosure specifically provides double-strandedRNAi agents comprising at least 15 to at least 19 or more contiguousnucleotides of KRAS. In particular, the present disclosure providesagents comprising sequences of 15 or more contiguous nucleotidesdiffering by 0, 1, 2 or 3 from those of the RNAi agents provided, e.g.,in Tables 1 to 6. The RNAi agents particularly can in one embodimentcomprise less than 30 nucleotides per strand, e.g., such as 17-23nucleotides, 15-19, 18-22 nucleotides, and/or 19-21 nucleotides, and/orsuch as those provided, e.g., in Tables 1 to 6, and modified andunmodified variants thereof (e.g., wherein the sense and/or anti-senseor first and/or second strand are modified or unmodified). The presentdisclosure also provides agents comprising a sense strand and ananti-sense strand, wherein the sense and/or the anti-sense strandcomprise sequences of 19 or more contiguous nucleotides differing by 0,1, 2 or 3 from those of the RNAi agents provided, e.g., in Tables 1 to6, and modified or unmodified variants thereof. The sense and anti-sensestrand can be contiguous, or covalently bounds, e.g., via a loop orlinker. The RNAi agents particularly can in one embodiment comprise lessthan 30 nucleotides per strand, e.g., such as 17 to 23 nucleotides, 18to 22 nucleotides, and/or 19 to 21 nucleotides, and/or sequences such asthose provided, e.g., in Tables 1 to 6.

The double-stranded RNAi agents can have 0, 1 or 2 blunt ends, and/oroverhangs of 1, 2, 3 or 4 nucleotides (i.e., 1 to 4 nt) from one or both3′ and/or 5′ ends. The double-stranded RNAi agents can also optionallycomprise one or two 3′ caps and/or one or more modified nucleotides.Modified variants of sequences as provided herein include those that areotherwise identical but contain substitutions of a naturally-occurringnucleotide for a corresponding modified nucleotide.

Furthermore, the RNAi agent can either contain only naturally-occurringnucleotide subunits (e.g., ribonucleotides), or one or moremodifications to the sugar, phosphate or base of one or more of thereplacement nucleotide subunits, whether they comprise ribonucleotidesubunits or deoxyribonucleotide subunits or other related modifiedvariants. In one embodiment, modified variants of the disclosed RNAiagents have a thymidine (as RNA, or, preferably, DNA) replacing auridine, or have an inosine base. In some embodiments, the modifiedvariants of the disclosed RNAi agents can have a nick in the passengerstrand, mismatches between the guide and passenger strand, DNA replacingthe RNA of a portion of both the guide and passenger strand (e.g., theseed region), and/or a shortened passenger strand (e.g., 15, 16, 17 or18 nt). Once a functional guide strand is identified, modifications andvariants of the RNAi agent can be readily made. Any combination ofmodifications which is not mutually exclusive can be (e.g., thecombination of base modifications with shortened passenger strand; ornicked passenger strand and base modifications; or DNA replacing part orall of the seed region and base modifications in the remaining RNA;etc.).

In one embodiment, modified variants of the disclosed RNAi agentsinclude RNAi agents with the same sequence (e.g., the same sequence ofbases) as disclosed in Tables 1 to 6, but with one or more modificationsto one or more of the sugar or phosphate of one or more of thenucleotide subunits. In one embodiment, the modifications improveefficacy, stability (e.g., against nucleases in, for example, bloodserum or intestinal fluid), and/or reduce immunogenicity of the RNAiagent. One aspect of the present disclosure relates to a double-strandedoligonucleotide comprising at least one non-natural nucleobase. Incertain embodiments, the non-natural nucleobase is difluorotolyl,nitroindolyl, nitropyrrolyl, or nitroimidazolyl. In a particularembodiment, the non-natural nucleobase is difluorotolyl. In certainembodiments, only one of the two oligonucleotide strands contains anon-natural nucleobase. In certain embodiments, both of theoligonucleotide strands contain a non-natural nucleobase.

The RNAi agent(s) can optionally be attached to a ligand selected toimprove one or more characteristic, such as, e.g., stability,distribution and/or cellular uptake of the agent, e.g., cholesterol or aderivative thereof. The RNAi agent(s) can be isolated or be part of apharmaceutical composition used for the methods described herein.Particularly, the pharmaceutical composition can be formulated fordelivery to specific tissues (e.g., those afflicted with a KRAS-relateddisease) or formulated for parenteral administration. The pharmaceuticalcomposition can optionally comprise two or more RNAi agents, each onedirected to the same or a different segment of the KRAS mRNA.Optionally, the pharmaceutical composition can further comprise or beused in conjunction with any known treatment for any KRAS-relateddisease.

The present disclosure further provides methods for reducing the levelof KRAS mRNA in a cell, particularly in the case of a diseasecharacterized by over-expression or hyper-activity of KRAS. Cellscomprising an alteration such as a mutation, over-expression and/orhyperactivity of KRAS are termed “KRAS-defective” cells. Such methodscomprise the step of administering one or more of the RNAi agents of thepresent disclosure to a cell, as further described below. The presentmethods utilize the cellular mechanisms involved in RNA interference toselectively degrade the target RNA in a cell and are comprised of thestep of contacting a cell with one or more of the RNAi agents of thepresent disclosure.

The present disclosure further provides methods for reducing the levelof KRAS mRNA in a cell, particularly in the case of a diseasecharacterized by over-expression, mutation or hyper-activity of KRAS.Such methods comprise the step of administering one or more of the RNAiagents of the present disclosure to a cell, as further described below.The present methods utilize the cellular mechanisms involved in RNAinterference to selectively degrade the target RNA in a cell and arecomprised of the step of contacting a cell with one or more of the RNAiagents of the present disclosure.

The present disclosure also encompasses a method of treating a humansubject having a pathological state mediated at least in part by KRASexpression, the method comprising the step of administering to thesubject a therapeutically effective amount of a RNAi agent targetingKRAS. Additional methods involve preventing, treating, modulating and/orameliorating a pathological state wherein disease progression (e.g.,tumor growth) requires KRAS, although KRAS is not amplified,over-expressed or mis-localized. Such methods comprise the step ofadministering one or more of the RNAi agents of the present disclosureto a subject, as further described below. The present methods utilizethe cellular mechanisms involved in RNA interference to selectivelydegrade the target RNA in a cell comprise the step of contacting a cellwith one or more of the RNAi agents of the present disclosure. Suchmethods can be performed directly on a cell or can be performed on amammalian subject by administering to a subject one or more of the RNAiagents/pharmaceutical compositions of the present disclosure. Reductionof target KRAS RNA in a cell results in a reduction in the amount ofencoded KRAS protein produced. In an organism, this can result inrestoration of balance in a pathway involving KRAS, and/or prevention ofKRAS accumulation, and/or a reduction in KRAS activity and/orexpression, and/or prevention of KRAS-mediated activation of othergenes, and/or amelioration, treatment and/or prevention of aKRAS-related disease. In one embodiment, a reduction in KRAS expression,level or activity can limit tumor growth.

The methods and compositions of the present disclosure, e.g., themethods and KRAS RNAi agent compositions, can be used in any appropriatedosage and/or formulation described herein or known in the art, as wellas with any suitable route of administration described herein or knownin the art.

The details of one or more embodiments of the present disclosure are setforth in the accompanying drawings and the description below. Elementsof the various embodiments (e.g., sequences, modifications, endcaps,combinations of RNAi agents, combination therapy involving a KRAS RNAiagent and another agent, etc.) which are not mutually-exclusive can becombined with each other as described herein and as known or developedin the art. For example, any RNAi agent sequence disclosed herein can becombined with any set of modifications or endcaps disclosed herein. Anycombination of modifications, 5′ end caps, and/or 3′ end caps can beused with any RNAi agent sequence disclosed herein. Any RNAi agentdisclosed herein (with any combination of modifications or endcaps orwithout either modifications or endcaps) can be combined with any otherRNAi agent or other treatment composition or method disclosed herein.

Other features, objects, and advantages of the present disclosure willbe apparent from this description, the drawings, and from the claims.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 illustrates various modified nucleotides: U002, U003, U004, U005,C004, C005, A004, A005, G005, and G004, which can be used in the RNAiagents disclosed herein. U002 indicates a 2′-deoxy-thymidine which isDNA. U003 indicates 2′-deoxy uridine. U004 indicates a nucleotide with aUridine (“U”) base with a 2′-O-methyl modification. U005 indicates a Ubase with a 2′-O-methoxyethyl (MOE) modification. C004 indicates aCysteine (“C”) base with a 2′-O-methyl modification. C005 indicates a Cbase with 2′-O-methoxyethyl modification. A004 indicates an Adenosine(“A”) base with a 2′-O-methyl modification. A005 indicates an A basewith 2′-O-methoxyethyl modification. G005 indicates a Guanosine (“G”)base with a 2′O-methyl modification. G004 indicates a G base with a2′O-methyl modification.

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure encompasses RNAi agents to KRAS, for targetingand inhibition of the KRAS gene, which are useful in treatment ofKRAS-related diseases (e.g., diseases associated with mutations inand/or altered expression, level and/or activity of KRAS, and/ordiseases which require KRAS, and/or diseases treatable by modulating theexpression, level and/or activity of KRAS), such as a proliferativedisease, including without limitation a solid or liquid cancer,adenocarcinoma, colorectal cancer, advanced and/or metastatic colorectalcancer, colon cancer, lung, non-small cell lung cancer and lungadenocarcinoma, acute myelogenous lung, bladder, brain, breast,cervical, endometrial, gastric, head and neck, kidney, leukemia,myelodysplastic syndrome, myeloid leukemia, liver or hepatic, melanoma,ovarian, pancreatic, prostate, testicular, thyroid cancers, andcardio-facio-cutaneous (CFC) syndrome and Noonan syndrome, and similarand related diseases. The present disclosure also provides methods oftreating a human subject having a pathological state mediated at leastin part by KRAS expression or over-expression or hyper-activity, themethod comprising the step of administering to the subject atherapeutically effective amount of a RNAi agent to KRAS.

Various Embodiments of the Present Disclosure Include the Following.

In one embodiment, the present disclosure relates to a compositioncomprising a RNAi agent comprising a sense strand and an antisensestrand, wherein the antisense strand comprises at least 15 contiguousnucleotides differing by 0, 1, 2, or 3 nucleotides from the antisensestrand of a RNAi agent specific to KRAS (or any set of overlapping RNAiagents specific to KRAS) provided, e.g., in any of Tables 1 to 6. Inanother embodiment, the present disclosure relates to a compositioncomprising a RNAi agent comprising a sense and an anti-sense strand,wherein the sense strand comprises at least 15 contiguous nucleotidesdiffering by 0, 1, 2, or 3 nucleotides from the sense strand of a RNAiagent from any sequence provided herein. In another embodiment, thepresent disclosure relates to a composition comprising a RNAi agentcomprising a first strand and a second strand, wherein the first strandcomprises at least 15 contiguous nucleotides differing by 0, 1, 2, or 3nucleotides from the sequence of the first strand, and the second strandcomprises at least 15 contiguous nucleotides differing by 0, 1, 2, or 3nucleotides from the sequence of the second strand of any RNAi agentprovided herein.

Particular duplexes include the example unmodified (e.g., “generic”) andexample modified sequences listed in Table 1. In addition to thedescribed example modifications, other modified variants arecontemplated and can be made using the nucleotide sequences provided. Invarious embodiments, the first and/or second strand are modified orunmodified or a combination of one modified and one unmodified.

RNAi Agents Comprising an Antisense and a Sense Strand Described Herein

In one embodiment, the present disclosure relates to a compositioncomprising a RNAi agent comprising an antisense strand, wherein theantisense strand comprises at least 15 contiguous nucleotides differingby 0, 1, 2, or 3 nucleotides from the antisense strand of a RNAi agentto KRAS selected from any sequence (or overlapping set of sequences)provided in a table herein (e.g., any of Tables 1 to 6). In oneembodiment, the present disclosure relates to a composition comprising aRNAi agent comprising a sense strand and an antisense strand, whereinthe antisense strand comprises at least 15 contiguous nucleotidesdiffering by 0 nucleotides from the antisense strand of a RNAi agent toKRAS selected from any sequence (or overlapping set of sequences)provided in a table here (e.g., any of Tables 1 to 6). In anotherembodiment, the present disclosure relates to a composition comprising aRNAi agent comprising a sense and an anti-sense strand, wherein thesequence of the anti-sense strand comprises the sequence of theanti-sense strand of a RNAi agent from any sequence provided herein. Inanother embodiment, the present disclosure relates to a compositioncomprising a RNAi agent comprising a first strand and a second strand,wherein the sequence of the first strand is the sequence of the firststrand of any RNAi agent provided herein. Particular duplexes includethose specific duplexes provided above and as listed in any one or moreof Table 1. Additional modified sequences (e.g., sequences comprisingone or more modified base) of each of the compositions above are alsocontemplated as part of the present disclosure.

TABLE 1 SEQ ID NOs. for RNAi Agents to KRAS Table 1. SEQ ID NOs forunmodified and example modified sequences of a first and a second strand(e.g., sense and anti-sense strand) for RNAi agents to KRAS UNMOD- SE-IFIED EXAM- QUENCES SE- ANTI- PLE MOD- ANTI- QUENCES SENSE IFIED SENSESENSE SEQ SEQ SENSE SEQ SEQ Duplex ID NO: ID NO: ID NO: ID NO:AD-35523.3 1 428 855 1282 AD-35529.1 2 429 856 1283 AD-35535.4 3 430 8571284 AD-35541.4 4 431 858 1285 AD-35547.4 5 432 859 1286 AD-35553.4 6433 860 1287 AD-35559.4 7 434 861 1288 AD-35565.4 8 435 862 1289AD-35524.4 9 436 863 1290 AD-35530.4 10 437 864 1291 AD-35536.4 11 438865 1292 AD-35542.4 12 439 866 1293 AD-35548.4 13 440 867 1294AD-35554.4 14 441 868 1295 AD-35560.2 15 442 869 1296 AD-35566.4 16 443870 1297 AD-35525.2 17 444 871 1298 AD-35531.4 18 445 872 1299AD-35537.4 19 446 873 1300 AD-35543.2 20 447 874 1301 AD-35549.4 21 448875 1302 AD-35555.4 22 449 876 1303 AD-35561.4 23 450 877 1304AD-35567.4 24 451 878 1305 AD-35526.4 25 452 879 1306 AD-35532.4 26 453880 1307 AD-35538.4 27 454 881 1308 AD-35544.4 28 455 882 1309AD-35550.4 29 456 883 1310 AD-35556.4 30 457 884 1311 AD-35562.4 31 458885 1312 AD-35568.4 32 459 886 1313 AD-35527.4 33 460 887 1314AD-35533.4 34 461 888 1315 AD-35539.4 35 462 889 1316 AD-35545.4 36 463890 1317 AD-35551.4 37 464 891 1318 AD-35563.4 38 465 892 1319AD-35528.4 39 466 893 1320 AD-35540.4 40 467 894 1321 AD-35546.4 41 468895 1322 AD-35552.4 42 469 896 1323 AD-35558.4 43 470 897 1324AD-35564.4 44 471 898 1325 AD-35570.4 45 472 899 1326 AD-35571.4 46 473900 1327 AD-35577.4 47 474 901 1328 AD-35583.4 48 475 902 1329AD-35589.4 49 476 903 1330 AD-35595.4 50 477 904 1331 AD-35601.4 51 478905 1332 AD-35607.4 52 479 906 1333 AD-35613.4 53 480 907 1334AD-35572.4 54 481 908 1335 AD-35578.4 55 482 909 1336 AD-35584.4 56 483910 1337 AD-35590.4 57 484 911 1338 AD-35596.4 58 485 912 1339AD-35602.4 59 486 913 1340 AD-35608.4 60 487 914 1341 AD-35614.4 61 488915 1342 AD-35573.4 62 489 916 1343 AD-35579.4 63 490 917 1344AD-35585.4 64 491 918 1345 AD-35591.4 65 492 919 1346 AD-35597.4 66 493920 1347 AD-35603.4 67 494 921 1348 AD-35609.4 68 495 922 1349AD-35615.4 69 496 923 1350 AD-35574.4 70 497 924 1351 AD-35580.1 71 498925 1352 AD-35586.4 72 499 926 1353 AD-35592.4 73 500 927 1354AD-35598.4 74 501 928 1355 AD-35604.4 75 502 929 1356 AD-35610.4 76 503930 1357 AD-35616.4 77 504 931 1358 AD-35575.4 78 505 932 1359AD-35581.4 79 506 933 1360 AD-35587.4 80 507 934 1361 AD-35593.4 81 508935 1362 AD-35599.4 82 509 936 1363 AD-35605.4 83 510 937 1364AD-35611.4 84 511 938 1365 AD-35617.4 85 512 939 1366 AD-35576.4 86 513940 1367 AD-35588.4 87 514 941 1368 AD-35667.1 88 515 942 1369AD-35673.1 89 516 943 1370 AD-35679.1 90 517 944 1371 AD-35685.1 91 518945 1372 AD-35691.1 92 519 946 1373 AD-35557.1 93 520 947 1374AD-35618.1 94 521 948 1375 AD-35569.1 95 522 949 1376 AD-35534.1 96 523950 1377 AD-35582.1 97 524 951 1378 AD-35594.1 98 525 952 1379AD-35600.1 99 526 953 1380 AD-35606.1 100 527 954 1381 AD-35612.1 101528 955 1382 AD-38127.1 102 529 956 1383 AD-38133.1 103 530 957 1384AD-38139.1 104 531 958 1385 AD-38145.1 105 532 959 1386 AD-38151.1 106533 960 1387 AD-38157.1 107 534 961 1388 AD-38163.1 108 535 962 1389AD-38169.1 109 536 963 1390 AD-38128.1 110 537 964 1391 AD-38134.1 111538 965 1392 AD-38140.1 112 539 966 1393 AD-38146.1 113 540 967 1394AD-38152.1 114 541 968 1395 AD-38158.1 115 542 969 1396 AD-38164.1 116543 970 1397 AD-38170.1 117 544 971 1398 AD-38129.1 118 545 972 1399AD-38135.1 119 546 973 1400 AD-38141.1 120 547 974 1401 AD-38147.1 121548 975 1402 AD-38153.1 122 549 976 1403 AD-38159.1 123 550 977 1404AD-38165.1 124 551 978 1405 AD-38171.1 125 552 979 1406 AD-38130.1 126553 980 1407 AD-38136.1 127 554 981 1408 AD-38142.1 128 555 982 1409AD-38148.1 129 556 983 1410 AD-38154.1 130 557 984 1411 AD-38160.1 131558 985 1412 AD-38166.1 132 559 986 1413 AD-38172.1 133 560 987 1414AD-38131.1 134 561 988 1415 AD-38137.1 135 562 989 1416 AD-38143.1 136563 990 1417 AD-38149.1 137 564 991 1418 AD-38155.1 138 565 992 1419AD-38161.1 139 566 993 1420 AD-38167.1 140 567 994 1421 AD-38173.1 141568 995 1422 AD-38132.1 142 569 996 1423 AD-38138.1 143 570 997 1424AD-38144.1 144 571 998 1425 AD-38150.1 145 572 999 1426 AD-38156.1 146573 1000 1427 AD-38162.1 147 574 1001 1428 AD-38168.1 148 575 1002 1429AD-38174.1 149 576 1003 1430 AD-39683.1 150 577 1004 1431 AD-39689.1 151578 1005 1432 AD-39695.1 152 579 1006 1433 AD-39701.1 153 580 1007 1434AD-39707.1 154 581 1008 1435 AD-39713.1 155 582 1009 1436 AD-39719.1 156583 1010 1437 AD-39725.1 157 584 1011 1438 AD-39684.1 158 585 1012 1439AD-39690.1 159 586 1013 1440 AD-39696.1 160 587 1014 1441 AD-39702.1 161588 1015 1442 AD-39708.1 162 589 1016 1443 AD-39714.1 163 590 1017 1444AD-39720.1 164 591 1018 1445 AD-39726.1 165 592 1019 1446 AD-39685.1 166593 1020 1447 AD-39691.1 167 594 1021 1448 AD-39697.1 168 595 1022 1449AD-39703.1 169 596 1023 1450 AD-39709.1 170 597 1024 1451 AD-39715.1 171598 1025 1452 AD-39721.1 172 599 1026 1453 AD-39727.1 173 600 1027 1454AD-39686.1 174 601 1028 1455 AD-39692.1 175 602 1029 1456 AD-39698.1 176603 1030 1457 AD-39704.1 177 604 1031 1458 AD-39710.1 178 605 1032 1459AD-39716.1 179 606 1033 1460 AD-39722.1 180 607 1034 1461 AD-39728.1 181608 1035 1462 AD-39687.1 182 609 1036 1463 AD-39693.1 183 610 1037 1464AD-39699.1 184 611 1038 1465 AD-39705.1 185 612 1039 1466 AD-39711.1 186613 1040 1467 AD-39717.1 187 614 1041 1468 AD-39723.1 188 615 1042 1469AD-39729.1 189 616 1043 1470 AD-39688.1 190 617 1044 1471 AD-39694.1 191618 1045 1472 AD-39700.1 192 619 1046 1473 AD-39706.1 193 620 1047 1474AD-39712.1 194 621 1048 1475 AD-39718.1 195 622 1049 1476 AD-39724.1 196623 1050 1477 AD-39730.1 197 624 1051 1478 AD-39736.1 198 625 1052 1479AD-39742.1 199 626 1053 1480 AD-39748.1 200 627 1054 1481 AD-39754.1 201628 1055 1482 AD-39760.1 202 629 1056 1483 AD-39766.1 203 630 1057 1484AD-39772.1 204 631 1058 1485 AD-39731.1 205 632 1059 1486 AD-39737.1 206633 1060 1487 AD-39743.1 207 634 1061 1488 AD-39749.1 208 635 1062 1489AD-39755.1 209 636 1063 1490 AD-39761.1 210 637 1064 1491 AD-39767.1 211638 1065 1492 AD-39773.1 212 639 1066 1493 AD-39732.1 213 640 1067 1494AD-39738.1 214 641 1068 1495 AD-39744.1 215 642 1069 1496 AD-39750.1 216643 1070 1497 AD-39756.1 217 644 1071 1498 AD-39762.1 218 645 1072 1499AD-39768.1 219 646 1073 1500 AD-39774.1 220 647 1074 1501 AD-39733.1 221648 1075 1502 AD-39739.1 222 649 1076 1503 AD-39745.1 223 650 1077 1504AD-39751.1 224 651 1078 1505 AD-39757.1 225 652 1079 1506 AD-39763.1 226653 1080 1507 AD-39769.1 227 654 1081 1508 AD-39775.1 228 655 1082 1509AD-39734.1 229 656 1083 1510 AD-39740.1 230 657 1084 1511 AD-39746.1 231658 1085 1512 AD-39752.1 232 659 1086 1513 AD-39758.1 233 660 1087 1514AD-39764.1 234 661 1088 1515 AD-39770.1 235 662 1089 1516 AD-39776.1 236663 1090 1517 AD-39735.1 237 664 1091 1518 AD-39741.1 238 665 1092 1519AD-39747.1 239 666 1093 1520 AD-39753.1 240 667 1094 1521 AD-39759.1 241668 1095 1522 AD-39765.1 242 669 1096 1523 AD-39771.1 243 670 1097 1524AD-39778.1 244 671 1098 1525 AD-39784.1 245 672 1099 1526 AD-39790.1 246673 1100 1527 AD-39796.1 247 674 1101 1528 AD-39802.1 248 675 1102 1529AD-39808.1 249 676 1103 1530 AD-39814.1 250 677 1104 1531 AD-39820.1 251678 1105 1532 AD-39779.1 252 679 1106 1533 AD-39785.1 253 680 1107 1534AD-39791.1 254 681 1108 1535 AD-39797.1 255 682 1109 1536 AD-39803.1 256683 1110 1537 AD-39809.1 257 684 1111 1538 AD-39815.1 258 685 1112 1539AD-39821.1 259 686 1113 1540 AD-39780.1 260 687 1114 1541 AD-39786.1 261688 1115 1542 AD-39792.1 262 689 1116 1543 AD-39798.1 263 690 1117 1544AD-39804.1 264 691 1118 1545 AD-39810.1 265 692 1119 1546 AD-39816.1 266693 1120 1547 AD-39822.1 267 694 1121 1548 AD-39781.1 268 695 1122 1549AD-39787.1 269 696 1123 1550 AD-39793.1 270 697 1124 1551 AD-39799.1 271698 1125 1552 AD-39805.1 272 699 1126 1553 AD-39811.1 273 700 1127 1554AD-39817.1 274 701 1128 1555 AD-39823.1 275 702 1129 1556 AD-39782.1 276703 1130 1557 AD-39788.1 277 704 1131 1558 AD-39794.1 278 705 1132 1559AD-39800.1 279 706 1133 1560 AD-39806.1 280 707 1134 1561 AD-39812.1 281708 1135 1562 AD-39818.1 282 709 1136 1563 AD-39824.1 283 710 1137 1564AD-39783.1 284 711 1138 1565 AD-39789.1 285 712 1139 1566 AD-39795.1 286713 1140 1567 AD-39801.1 287 714 1141 1568 AD-39807.1 288 715 1142 1569AD-39813.1 289 716 1143 1570 AD-39819.1 290 717 1144 1571 AD-39825.1 291718 1145 1572 AD-39831.1 292 719 1146 1573 AD-39837.1 293 720 1147 1574AD-39843.1 294 721 1148 1575 AD-39849.1 295 722 1149 1576 AD-39855.1 296723 1150 1577 AD-39861.1 297 724 1151 1578 AD-39867.1 298 725 1152 1579AD-39826.1 299 726 1153 1580 AD-39832.1 300 727 1154 1581 AD-39838.1 301728 1155 1582 AD-39844.1 302 729 1156 1583 AD-39850.1 303 730 1157 1584AD-39856.1 304 731 1158 1585 AD-39862.1 305 732 1159 1586 AD-39868.1 306733 1160 1587 AD-39827.1 307 734 1161 1588 AD-39833.1 308 735 1162 1589AD-39839.1 309 736 1163 1590 AD-39845.1 310 737 1164 1591 AD-39851.1 311738 1165 1592 AD-39857.1 312 739 1166 1593 AD-39863.1 313 740 1167 1594AD-39869.1 314 741 1168 1595 AD-39828.1 315 742 1169 1596 AD-39834.1 316743 1170 1597 AD-39840.1 317 744 1171 1598 AD-39846.1 318 745 1172 1599AD-39852.1 319 746 1173 1600 AD-39858.1 320 747 1174 1601 AD-39864.1 321748 1175 1602 AD-39870.1 322 749 1176 1603 AD-39829.1 323 750 1177 1604AD-39835.1 324 751 1178 1605 AD-39841.1 325 752 1179 1606 AD-39853.1 326753 1180 1607 AD-39859.1 327 754 1181 1608 AD-39865.1 328 755 1182 1609AD-39871.1 329 756 1183 1610 AD-39830.1 330 757 1184 1611 AD-39836.1 331758 1185 1612 AD-39842.1 332 759 1186 1613 AD-39848.1 333 760 1187 1614AD-39854.1 334 761 1188 1615 AD-39860.1 335 762 1189 1616 AD-39866.1 336763 1190 1617 AD-39992.1 337 764 1191 1618 AD-39998.1 338 765 1192 1619AD-40004.1 339 766 1193 1620 AD-40010.1 340 767 1194 1621 AD-40016.1 341768 1195 1622 AD-40022.1 342 769 1196 1623 AD-40028.1 343 770 1197 1624AD-40034.1 344 771 1198 1625 AD-39999.1 345 772 1199 1626 AD-40005.1 346773 1200 1627 AD-40011.1 347 774 1201 1628 AD-40017.1 348 775 1202 1629AD-40029.1 349 776 1203 1630 AD-40035.1 350 777 1204 1631 AD-39994.1 351778 1205 1632 AD-40000.1 352 779 1206 1633 AD-40006.1 353 780 1207 1634AD-40012.1 354 781 1208 1635 AD-40018.1 355 782 1209 1636 AD-40024.1 356783 1210 1637 AD-40030.1 357 784 1211 1638 AD-40036.1 358 785 1212 1639AD-39995.1 359 786 1213 1640 AD-40001.1 360 787 1214 1641 AD-40007.1 361788 1215 1642 AD-40013.1 362 789 1216 1643 AD-40019.1 363 790 1217 1644AD-40025.1 364 791 1218 1645 AD-40031.1 365 792 1219 1646 AD-40037.1 366793 1220 1647 AD-39996.1 367 794 1221 1648 AD-40002.1 368 795 1222 1649AD-40008.1 369 796 1223 1650 AD-40014.1 370 797 1224 1651 AD-40020.1 371798 1225 1652 AD-40026.1 372 799 1226 1653 AD-40032.1 373 800 1227 1654AD-40038.1 374 801 1228 1655 AD-39997.1 375 802 1229 1656 AD-40009.1 376803 1230 1657 AD-40015.1 377 804 1231 1658 AD-40021.1 378 805 1232 1659AD-40027.1 379 806 1233 1660 AD-40033.1 380 807 1234 1661 AD-40039.1 381808 1235 1662 AD-40045.1 382 809 1236 1663 AD-40051.1 383 810 1237 1664AD-40057.1 384 811 1238 1665 AD-40063.1 385 812 1239 1666 AD-40069.1 386813 1240 1667 AD-40075.1 387 814 1241 1668 AD-40081.1 388 815 1242 1669AD-40040.1 389 816 1243 1670 AD-40046.1 390 817 1244 1671 AD-40052.1 391818 1245 1672 AD-40058.1 392 819 1246 1673 AD-40064.1 393 820 1247 1674AD-40070.1 394 821 1248 1675 AD-40076.1 395 822 1249 1676 AD-40082.1 396823 1250 1677 AD-40041.1 397 824 1251 1678 AD-40047.1 398 825 1252 1679AD-40053.1 399 826 1253 1680 AD-40059.1 400 827 1254 1681 AD-40065.1 401828 1255 1682 AD-40071.1 402 829 1256 1683 AD-40077.1 403 830 1257 1684AD-40083.1 404 831 1258 1685 AD-40042.1 405 832 1259 1686 AD-40048.1 406833 1260 1687 AD-40054.1 407 834 1261 1688 AD-40060.1 408 835 1262 1689AD-40066.1 409 836 1263 1690 AD-40072.1 410 837 1264 1691 AD-40078.1 411838 1265 1692 AD-40084.1 412 839 1266 1693 AD-40043.1 413 840 1267 1694AD-40049.1 414 841 1268 1695 AD-40055.1 415 842 1269 1696 AD-40061.1 416843 1270 1697 AD-40067.1 417 844 1271 1698 AD-40073.1 418 845 1272 1699AD-40079.1 419 846 1273 1700 AD-40085.1 420 847 1274 1701 AD-40044.1 421848 1275 1702 AD-40050.1 422 849 1276 1703 AD-40056.1 423 850 1277 1704AD-40062.1 424 851 1278 1705 AD-40068.1 425 852 1279 1706 AD-40074.1 426853 1280 1707 AD-40080.1 427 854 1281 1708 AD-39720.1 1716 1754 17921830 AD-39706.1 1717 1755 1793 1831 AD-39712.1 1718 1756 1794 1832AD-39760.1 1719 1757 1795 1833 AD-39732.1 1720 1758 1796 1834 AD-35541.41721 1759 1797 1835 AD-39735.1 1722 1760 1798 1836 AD-39741.1 1723 17611799 1837 AD-39778.1 1724 1762 1800 1838 AD-39790.1 1725 1763 1801 1839AD-39822.1 1726 1764 1802 1840 AD-35609.4 1727 1765 1803 1841 AD-35581.41728 1766 1804 1842 AD-39845.1 1729 1767 1805 1843 AD-39858.1 1730 17681806 1844 AD-39870.1 1731 1769 1807 1845 AD-35576.4 1732 1770 1808 1846AD-35588.4 1733 1771 1809 1847 AD-35600.1 1734 1772 1810 1848 AD-35606.11735 1773 1811 1849 AD-38151.1 1736 1774 1812 1850 AD-38163.1 1737 17751813 1851 AD-39999.1 1738 1776 1814 1852 AD-38159.1 1739 1777 1815 1853AD-38130.1 1740 1778 1816 1854 AD-38136.1 1741 1779 1817 1855 AD-40036.11742 1780 1818 1856 AD-40008.1 1743 1781 1819 1857 AD-40021.1 1744 17821820 1858 AD-40077.1 1745 1783 1821 1859 AD-40072.1 1746 1784 1822 1860AD-40061.1 1747 1785 1823 1861 AD-40068.1 1748 1786 1824 1862 AD-38131.11749 1787 1825 1863 AD-38167.1 1750 1788 1826 1864 KRAS1273 1751 17891827 1865 31273_A22S26 KRAS2892 1752 1790 1828 1866 2892_A37S26 KRAS47311753 1791 1829 1867 4731_A22S26 AD-39741.1 2770 2760 AD-39735.1 27712761 AD-38159.1 2772 2762 NA 2773 2763 AD-38130.1 2774 2764 NA 2775 2765NA 2776 2766 AD-38136.1 2777 2767 AD-40061.1 2778 2768 AD-35588.4 27792769 AD-39845.1 2790 2780 AD-39720.1 2791 2781 AD-35581.4 2792 2782AD-40068.1 2793 2783 AD-39778.1 2794 2784 AD-35606.1 2795 2785AD-35609.4 2796 2786 AD-38163.1 2797 2787 AD-35600.1 2798 2788AD-40008.1 2799 2789 AD-40036.1 2810 2800 AD-39790.1 2811 2801AD-39870.1 2812 2802 AD-38131.1 2813 2803 AD-40077.1 2814 2804AD-38167.1 2815 2805 AD-38151.1 2816 2806 AD-39858.1 2817 2807AD-39706.1 2818 2808 AD-40021.1 2819 2809 AD-39760.1 2828 2820AD-39822.1 2829 2821 AD-39999.1 2830 2822 AD-40072.1 2831 2823AD-39732.1 2832 2824 AD-35576.4 2833 2825 AD-39712.1 2834 2826AD-35541.4 2835 2827

Provided in Table 1 are the nickname of various KRAS RNAi duplexes; theSEQ ID NOs. of unmodified (e.g., “generic”) sense and anti-sensesequences; and the SEQ ID NOs. for example sense and anti-sense strands.

Table 1, below, provides the SEQ ID NOs for the unmodified and anexample modified sequence of the sense and an anti-sense strands ofvarious RNAi agents to KRAS. The base composition of each sequencerepresented by a SEQ ID NO is provided in more detail in Tables 2 and 3.Table 4 shows overlapping groups of these KRAS RNAi agents. Tables 5 and6 show efficacy of various KRAS RNAi agents.

Table 1 presents the SEQ ID identifiers of an example unmodified firstand second strand of each KRAS RNAi agent; the Table also provides anexample modified sequence for each KRAS RNAi agent. For example, inTable 1, the unmodified sequences of example KRAS RNAi agent nicknamedAD-35523.3 are SEQ ID NOs: 1 and 428. An example set of modifiedsequences for this duplex is represented by SEQ ID NOs: 855 and 1282.Also note that the “AD” prefix of the nickname is on occasion replacedby “ND”. The name of the RNAi also sometimes has a suffix, such as 0.1.This indicates a particular variant of a duplex. Thus, AD-35523.1,AD-35523.2, AD-35523.3, ND-35523 and the like all indicate KRAS RNAiagents of the same sequence, although they may differ in how they aremodified. In these cases, replacement of a U with a T is considered amodification that does not introduce a mismatch; thus, two otherwiseidentical sequences wherein one or more U bases are replaced by T arestill considered to be identical and the same. Some nicknames of RNAiagents also comprise the suffix “b1”, indicating “batch 1.” The variousKRAS RNAi agents comprising the nickname AD-35523 thus all have the samebase sequence (though not necessarily the same modification), and thesuffix “b1” (or “b2” or the like) may indicate a particular batch,though these also have the same sequence.

Some RNAi agents in Table 1 have alternative names or nicknames. Somenicknames are derived from their position in the KRAS gene and, often, acode for the format for modifications. It is noted, however, thatdifferent methodologies are available for numbering the KRAS genesequence. The numbering used herein for the KRAS gene is forillustration only. Alternative names of some duplexes are listed below:

TABLE 1.1 Alternative Names of some RNAi Agents Duplex Name NicknameAD-39741.1 hs_KRAS_322_A22S26 AD-38159.1 hs_KRAS_528_A22S26 AD-39735.1hs_KRAS_321_A22S26 AD-38130.1 hs_KRAS_531_A22S26

NA, not applicable.

Additional alternative names are provided in Tables 1, 2 and 3. Forexample, hs_KRAS 1273_A22S26, hs_KRAS 2892_A37S26, and hs_KRAS4731_A22S26 are also sometimes alternatively designated KRAS1273,KRAS2892, and KRAS4731, respectively.

TABLE 1.2 Additional Alternative Names of some RNAi Agents AD SEQ SEQnick- Nickname ID Sense 19mer ID name siRNA Guide 19mer generic NO.generic NO. AD- hs KRAS ATCAATTACTACTTGCTTC 2760 GAAGCAAGTAGTAAT 277039741.1 322 TGAT A22S26 AD- hs KRAS TCAATTACTACTTGCTTCC 2761GGAAGCAAGTAGTAA 2771 39735.1 321 TTGA A22S26 AD- hs KRASTTTCCTACTAGGACCATAG 2762 CTATGGTCCTAGTAG 2772 38159.1 528 GAAA A22S26 NAhs KRAS TAACTTTACATTCATCAGG 2763 CCTGATGAATGTAAA 2773 1273 GTTA A22S26AD- hs KRAS TTATTTCCTACTAGGACCA 2764 TGGTCCTAGTAGGAA 2774 38130.1 531ATAA A22S26 NA hs KRAS AATCTAGTTATGACTATTC 2765 GAATAGTCATAACTA 27754731 GATT A22S26 NA hs KRAS TATCTTTATTAAATTCTCC 2766 GGAGAATTTAATAAA2776 2892 GATA A37S26 AD- NA TTTATTTCCTACTAGGACC 2767 GGTCCTAGTAGGAAA2777 38136.1 TAAA AD- NA AATTCCATAACTTCTTGCT 2768 AGCAAGAAGTTATGG 277840061.1 AATT AD- NA TCTATAATGGTGAATATCT 2769 AGATATTCACCATTA 277935588.4 TAGA AD- NA GATTTAGTATTATTTATGG 2780 CCATAAATAATACTA 279039845.1 AATC AD- NA AGCTCCAACTACCACAAGT 2781 ACTTGTGGTAGTTGG 279139720.1 AGCT AD- NA TTATTTATGGCAAATACAC 2782 GTGTATTTGCCATAA 279235581.4 ATAA AD- NA AATAAAAGGAATTCCATAA 2783 TTATGGAATTCCTTT 279340068.1 TATT AD- NA TTCTCCATCAATTACTACT 2784 AGTAGTAATTGATGG 279439778.1 AGAA AD- NA TTCTCTATAATGGTGAATA 2785 TATTCACCATTATAG 279535606.1 AGAA AD- NA AAATACACAAAGAAAGCCC 2786 GGGCTTTCTTTGTGT 279635609.4 ATTT AD- NA TTTAATTTGTTCTCTATAA 2787 TTATAGAGAACAAAT 279738163.1 TAAA AD- NA TCTCTATAATGGTGAATAT 2788 ATATTCACCATTATA 279835600.1 GAGA AD- NA TCTAGAAGGCAAATCACAT 2789 ATGTGATTTGCCTTC 279940008.1 TAGA AD- NA AATCACATTTATTTCCTAC 2800 GTAGGAAATAAATGT 281040036.1 GATT AD- NA GTTTCTCCATCAATTACTA 2801 TAGTAATTGATGGAG 281139790.1 AAAC AD- hs KRAS ATATCTTCAAATGATTTAG 2802 CTAAATCATTTGAAG 281239870.1 459 ATAT A37S26 AD- NA TTTCAATAAAAGGAATTCC 2803 GGAATTCCTTTTATT2813 38131.1 GAAA AD- NA CTTGCTAAGTCCTGAGCCT 2804 AGGCTCAGGACTTAG 281440077.1 CAAG AD- NA CTGATGTTTCAATAAAAGG 2805 CCTTTTATTGAAACA 281538167.1 TCAG AD- NA TAATTTGTTCTCTATAATG 2806 CATTATAGAGAACAA 281638151.1 ATTA AD- NA ATCTTCAAATGATTTAGTA 2807 TACTAAATCATTTGA 281739858.1 AGAT AD- NA ATCGTCAAGGCACTCTTGC 2808 GCAAGAGTGCCTTGA 281839706.1 CGAT AD- NA TGTCTACTGTTCTAGAAGG 2809 CCTTCTAGAACAGTA 281940021.1 GACA AD- NA ATTAGCTGTATCGTCAAGG 2820 CCTTGACGATACAGC 282839760.1 TAAT AD- NA TCGAGAATATCCAAGAGAC 2821 GTCTCTTGGATATTC 282939822.1 TCGA AD- NA TCTTCAGAGTCCTTAACTC 2822 GAGTTAAGGACTCTG 283039999.1 AAGA AD- NA ATAACTTCTTGCTAAGTCC 2823 GGACTTAGCAAGAAG 283140072.1 TTAT AD- NA AATGATTCTGAATTAGCTG 2824 CAGCTAATTCAGAAT 283239732.1 CATT AD- NA TATAATGGTGAATATCTTC 2825 GAAGATATTCACCAT 283335576.4 TATA AD- NA TATCGTCAAGGCACTCTTG 2826 CAAGAGTGCCTTGAC 283439712.1 GATA AD- NA TATTGTTGGATCATATTCG 2827 CGAATATGATCCAAC 283535541.4 AATAAdditional siRNAs disclosed herein also have alternative names. Thesenames begin with AD. These alternative names, nicknames and sequences ofthe generic (unmodified) sequences are provided below. The targetsequence (DNA) corresponding to the Guide and Sense strand are provided.siRNAs include, for example, double-stranded RNA corresponding to theDNA sequences provided (e.g., as RNA with or without any of thefollowing or combination of any of the following: modification(s),terminal TT or other overhang(s), endcap(s), alternative base (LNA, PNA,etc.), and/or a few DNA bases interspersed among the RNA or other bases,etc.).Additional tables (e.g., Tables 1.1 and 1.2) are continuations of Table1; thus, references to any Table or Tables include references toadditional Tables. For example, references to Table 1 also includereferences to Tables 1.1 and 1.2; and references to Tables 1 to 6include Tables 1.1, 1.2, 6.1, 6.2, etc.

Various Embodiments of the Present Disclosure

Various RNAi agents to KRAS are disclosed in Tables 1 to 6.

Tables 1, 2 and 3 provide the sequence, SEQ ID NOs and relativepositions of various RNAi agents to KRAS, including both unmodifiedsequences (listed in Table 2) and example modified sequences (listed inTable 3).

In the sequences in Table 3, lower-case letters (e.g., c, u) indicatemodified nucleotides while upper case letters (e.g., C, U, A, G)indicate unmodified nucleotides. In this Table, example modifiedversions of each of the sequences are shown. However, the presentdisclosure also contemplates and encompasses unmodified versions ofthese sequences and other versions which comprise additional oralternative modifications. Thus, for example, AD-35523.3 can optionallyhave the unmodified sequences of SEQ ID NO: 1 in the sense strand andSEQ ID NO: 428 in the anti-sense strand. The present disclosure alsoencompasses alternative modified versions of the duplex comprising themodified sequences of SEQ ID NO: 855 in the sense strand and SEQ ID NO:1282 in the anti-sense strand. The present disclosure also encompassesdifferent modified variants of SEQ ID NO: 1 in the sense strand and SEQID NO: 428 in the anti-sense strand. Similarly, the present disclosurealso encompasses any modified variant of any unmodified sequencedisclosed herein.

In the sequences in Tables 1 to 3, the modified and unmodified sequencescan optionally comprise the sequence “TT”, “dTdT”, “dTsdT” or “UU” atthe 3′ end. Thus, in the example above, AD-35523.3 can optionally havethe modified sequences of SEQ ID NO: 855 in the sense strand and SEQ IDNO: 1282 in the anti-sense strand. As noted in Table 3, below, SEQ IDNO: 855 and SEQ ID NO: 1282 include a terminal dTdT. dT is2′-deoxy-thymidine-5′-phosphate and sdT is 2′-deoxy Thymidine5′-phosphorothioate. In the disclosed sequences, terminal dinucleotide“UU” is 2′-OMe-U 2′-OMe-U, and neither the terminal TT nor the terminalUU are in the inverted/reverse orientation. The terminal dithymidine (orUU) is not part of the KRAS target sequence, but is a modified variantof the dithymidine dinucleotide commonly placed as an overhang toprotect the ends of siRNAs from nucleases (see, for example, Elbashir etal. 2001 Nature 411: 494-498; Elbashir et al. 2001 EMBO J. 20:6877-6888; and Kraynack et al. 2006 RNA 12:163-176). A terminaldinucleotide is known from these references to enhance nucleaseresistance but not contribute to target recognition. Thus, the presentdisclosure also encompasses any modified or any unmodified sequencedisclosed herein, wherein the modified sequence comprises a terminal TT,dTdT, sdT, dTsdT, sdTsdT, sdTdT, or the like which may be in either theinverted/reverse orientation or in the same 5′ to 3′ orientation as theKRAS specific sequence in the duplex. In addition, terminology usedherein referring to “the KRAS portion of a RNAi agent sequence” and thelike indicate the portion of the sequence of a RNAi agent which isderived from KRAS (thus “the KRAS portion of a RNAi agent sequence” doesnot include, for example, a terminal dTdT, TT, UU, or the like, but doesinclude the portion of the RNAi agent that corresponds to or iscomplementary to a portion of the KRAS gene sequence or mRNA sequence.

On any modified or unmodified sequence, a 3′ end cap, as is known in theart, can be used instead of or in addition to a terminal dinucleotide tostabilize the end from nuclease degradation provided that the 3′ end capis able to both stablize the RNAi agent (e.g., against nucleases) andnot interfere excessively with siRNA activity. Thus, the presentdisclosure also encompasses any modified or any unmodified sequencedisclosed herein, wherein the modified sequence further comprises aterminal 3′ end cap.

Table 4 provides sets of overlapping RNAi agents to KRAS.

Activity levels of various KRAS RNAi agents are provided in Tables 5 and6.

An RNAi Agent Comprising an Anti-Sense Strand Described Herein

In one particular specific embodiment, the present disclosure relates toa composition comprising a RNAi agent comprising an anti-sense strand,wherein the anti-sense strand comprises at least 15 contiguousnucleotides differing by 0, 1, 2, or 3 nucleotides from the anti-sensestrand of a RNAi agent to KRAS selected from those anti-sense strands inthe specific duplexes provided herein and as listed, e.g., in Tables 1to 6.

Various specific embodiments of this embodiment are described below.

In one embodiment, the composition further comprises a second RNAi agentto KRAS. In various embodiments, the second RNAi agent is physicallyseparate from the first, or the two KRAS RNAi agents are physicallyconnected (e.g., covalently linked or otherwise conjugated) or combinedin the same pharmaceutical composition, or are both elements in the sametreatment regimen.

In one embodiment, the composition comprises a RNAi agent comprising afirst and an second strand, wherein the sequence of the first strand andthe sequence of the second strand are the sequences of the first andsecond strand, respectively, of any RNAi agent provided herein. In oneembodiment, the composition comprises a RNAi agent comprising a firstand an second strand, wherein the sequence of the first strand and thesequence of the second strand are the sequences of the first and secondstrand, respectively, of any RNAi agent provided herein, furthercomprising an additional about 6 to 20 nucleotides on one or bothstrands (e.g., about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19or 20 nt). In various embodiments, the first and second strands are thesense and anti-sense strands listed in the Tables herein, respectively.In various embodiments, the first and second strands are the anti-senseand sense strands listed in the Tables herein, respectively.

In one embodiment, the antisense strand is about 30 or fewer nt inlength.

In one embodiment, the sense strand and the antisense strand form aduplex region of about 15 to about 30 nucleotide pairs in length.

In one embodiment, the antisense strand is about 15 to about 36 nt inlength, including about 18 to about 30 nt in length, and furtherincluding about 19 to about 21 nt in length and about 19 to about 23 ntin length. In one embodiment, the antisense strand has at least thelength selected from about 15 nt, about 16 nt, about 17 nt, about 18 nt,about 19 nt, about 20 nt, about 21 nt, about 22 nt, about 23 nt, about24 nt, about 25 nt, about 26 nt, about 27 nt, about 28 nt, about 29 ntand about 30 nt.

In one embodiment, the RNAi agent comprises a modification that causesthe RNAi agent to have increased stability in a biological sample orenvironment, e.g., cytoplasm, interstitial fluids, blood serum, lung orintestinal lavage fluid.

In one embodiment, the RNAi agent comprises at least one sugar backbonemodification (e.g., phosphorothioate linkage) and/or at least one2′-modified nucleotide. In one embodiment, all the pyrimidines are 2′O-methyl-modified nucleotides.

In one embodiment, the RNAi agent comprises: at least one5′-uridine-adenine-3′ (5′-ua-3′) dinucleotide, wherein the uridine is a2′-modified nucleotide; and/or at least one 5′-uridine-guanine-3′(5′-ug-3′) dinucleotide, wherein the 5′-uridine is a 2′-modifiednucleotide; and/or at least one 5′-cytidine-adenine-3′ (5′-ca-3′)dinucleotide, wherein the 5′-cytidine is a 2′-modified nucleotide;and/or at least one 5′-uridine-uridine-3′ (5′-uu-3′) dinucleotide,wherein the 5′-uridine is a 2′-modified nucleotide.

In one embodiment, the RNAi agent comprises a 2′-modification selectedfrom the group consisting of: 2′-deoxy, 2′-deoxy-2′-fluoro, 2′-O-methyl,2′-O-methoxyethyl (2′-O-MOE), 2′-O-aminopropyl (2′-O-AP),2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-O-dimethylaminopropyl(2′-O-DMAP), 2′-O-dimethylaminoethyloxyethyl (2′-O-DMAEOE), and2′-O-N-methylacetamido (2′-O-NMA). In one embodiment, all thepyrimidines are 2′ O-methyl-modified nucleotides.

In one embodiment, the RNAi agent comprises a blunt end.

In one embodiment, the RNAi agent comprises an overhang having 1 to 4unpaired nucleotides.

In one embodiment, the RNAi agent comprises an overhang at the 3′-end ofthe antisense strand of the RNAi agent.

In one embodiment, the RNAi agent is ligated to one or more diagnosticcompound, reporter group, cross-linking agent, nuclease-resistanceconferring moiety, natural or unusual nucleobase, lipophilic molecule,cholesterol, lipid, lectin, steroid, uvaol, hecigenin, diosgenin,terpene, triterpene, sarsasapogenin, Friedelin,epifriedelanol-derivatized lithocholic acid, vitamin, carbohydrate,dextran, pullulan, chitin, chitosan, synthetic carbohydrate, oligolactate 15-mer, natural polymer, low- or medium-molecular weightpolymer, inulin, cyclodextrin, hyaluronic acid, protein, protein-bindingagent, integrin-targeting molecule, polycationic, peptide, polyamine,peptide mimic, and/or transferrin.

In one embodiment, the RNAi agent is capable of inhibiting expression ofKRAS by at least about 60% at a concentration of 10 nM in RKO cells invitro.

In one embodiment, the RNAi agent is capable of inhibiting expression ofKRAS by at least about 70% at a concentration of 10 nM in RKO cells invitro.

In one embodiment, the RNAi agent is capable of inhibiting expression ofKRAS by at least about 80% at a concentration of 10 nM in RKO cells invitro.

In one embodiment, the RNAi agent is capable of inhibiting expression ofKRAS by at least about 90% at a concentration of 10 nM in RKO cells invitro.

In one embodiment, the RNAi agent has an EC50 of no more than about 0.1nM in

MiaPaca2 cells.

In one embodiment, the RNAi agent has an EC50 of no more than about 0.01nM in MiaPaca2 cells.

In one embodiment, the RNAi agent has an EC50 of no more than about0.001 nM in MiaPaca2 cells.

A RNAi agent comprising a first and a second strand described herein

In one particular specific embodiment, the present disclosure relates toa composition comprising a RNAi agent comprising a first strand and asecond strand, wherein the sequence of the first strand comprises atleast 15 contiguous nucleotides, differing by 0, 1, 2, or 3 nucleotidesfrom the sequence of the first strand of a RNAi agent to KRAS selectedfrom the specific duplexes provided herein and listed, e.g., in Table 1.

In one particular specific embodiment, the present disclosure relates toa composition comprising a RNAi agent comprising a first strand and asecond strand, wherein the sequence of the first strand and/or secondstrand comprise at least 15 contiguous nucleotides, differing by 0, 1,2, or 3 nucleotides from the sequence of the first and/or second strandof a RNAi agent to KRAS selected from the specific duplexes providedherein and listed, e.g., in Table 1.

In one particular specific embodiment, the present disclosure relates toa composition comprising a RNAi agent comprising a first strand and asecond strand, wherein the sequence of the first strand and/or secondstrand comprise the sequence of the first and/or second strand,respectively, of a RNAi agent to KRAS selected from the specificduplexes provided herein and listed, e.g., in Table 1.

In one particular specific embodiment, the present disclosure relates toa composition comprising a RNAi agent comprising a first strand and asecond strand, wherein the sequence of the first strand and/or secondstrand are the sequence of the first and/or second strand, respectively,of a RNAi agent to KRAS selected from the specific duplexes providedherein and listed, e.g., in Table 1.

Various specific embodiments of these embodiments are described below.

In one embodiment, the composition further comprises a second RNAi agentto KRAS. In various embodiments, the second RNAi agent is physicallyseparate from the first, or the two are physically connected (e.g.,covalently linked or otherwise conjugated).

In one embodiment, the antisense strand is about 30 or fewer nt inlength.

In one embodiment, the sense strand and the antisense strand form aduplex region of about 15 to about 30 nt pairs in length.

In one embodiment, the antisense strand is about 15 to about 36 nt inlength including about 18 to about 23 nt in length, and including about19 to about 21 nt in length and about 19 to about 23 nt in length. Inone embodiment, the antisense strand has at least the length selectedfrom about 15 nt, about 16 nt, about 17 nt, about 18 nt, about 19 nt,about 20 nt, about 21 nt, about 22 nt, about 23 nt, about 24 nt, about25 nt, about 26 nt, about 27 nt, about 28 nt, about 29 nt and about 30nt.

In one embodiment, the RNAi agent comprises a modification that causesthe RNAi agent to have increased stability in a biological sample orenvironment, e.g., blood serum or intestinal lavage fluid.

In one embodiment, the RNAi agent comprises at least one sugar backbonemodification (e.g., phosphorothioate linkage) and/or at least one2′-modified nucleotide. In one embodiment, all the pyrimidines are 2′O-methyl-modified nucleotides.

In one embodiment, the RNAi agent comprises: at least one5′-uridine-adenine-3′ (5′-ua-3′) dinucleotide, wherein the uridine is a2′-modified nucleotide; and/or at least one 5′-uridine-guanine-3′(5′-ug-3′) dinucleotide, wherein the 5′-uridine is a 2′-modifiednucleotide; and/or at least one 5′-cytidine-adenine-3′ (5′-ca-3′)dinucleotide, wherein the 5′-cytidine is a 2′-modified nucleotide;and/or at least one 5′-uridine-uridine-3′ (5′-uu-3′) dinucleotide,wherein the 5′-uridine is a 2′-modified nucleotide.

In one embodiment, the RNAi agent comprises a 2′-modification selectedfrom the group consisting of: 2′-deoxy, 2′-deoxy-2′-fluoro, 2′-O-methyl,2′-O-methoxyethyl (2′-O-MOE), 2′-O-aminopropyl (2′-O-AP),2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-O-dimethylaminopropyl(2′-O-DMAP), 2′-O-dimethylaminoethyloxyethyl (2′-O-DMAEOE), and2′-O-N-methylacetamido (2′-O-NMA).

In one embodiment, the RNAi agent comprises a blunt end.

In one embodiment, the RNAi agent comprises an overhang having 1 to 4unpaired nucleotides.

In one embodiment, the RNAi agent comprises an overhang at the 3′-end ofthe antisense strand of the RNAi agent.

In one embodiment, the RNAi agent is ligated to one or more diagnosticcompound, reporter group, cross-linking agent, nuclease-resistanceconferring moiety, natural or unusual nucleobase, lipophilic molecule,cholesterol, lipid, lectin, steroid, uvaol, hecigenin, diosgenin,terpene, triterpene, sarsasapogenin, Friedelin,epifriedelanol-derivatized lithocholic acid, vitamin, carbohydrate,dextran, pullulan, chitin, chitosan, synthetic carbohydrate, oligolactate 15-mer, natural polymer, low- or medium-molecular weightpolymer, inulin, cyclodextrin, hyaluronic acid, protein, protein-bindingagent, integrin-targeting molecule, polycationic, peptide, polyamine,peptide mimic, and/or transferrin.

In one embodiment, the RNAi agent is capable of inhibiting expression ofKRAS by at least about 60% at a concentration of 10 nM in RKO cells invitro.

In one embodiment, the RNAi agent is capable of inhibiting expression ofKRAS by at least about 70% at a concentration of 10 nM in RKO cells invitro.

In one embodiment, the RNAi agent is capable of inhibiting expression ofKRAS by at least about 80% at a concentration of 10 nM in RKO cells invitro.

In one embodiment, the RNAi agent is capable of inhibiting expression ofKRAS by at least about 90% at a concentration of 10 nM in RKO cells invitro.

In one embodiment, the RNAi agent has an EC50 of no more than about 0.1nM in MiaPaca2 cells.

In one embodiment, the RNAi agent has an EC50 of no more than about 0.01nM in MiaPaca2 cells.

In one embodiment, the RNAi agent has an EC50 of no more than about0.001 nM in MiaPaca2 cells.

A Method of Treatment Using a RNAi Agent Described Herein

In one particular specific embodiment, the present disclosure relates toa method of treating a KRAS-related disease in an individual, comprisingthe step of administering to the individual a therapeutically effectiveamount of a composition comprising a RNAi agent comprising at least anantisense strand, wherein the antisense strand comprises at least 15 to19 contiguous nucleotides differing by 0, 1, 2, or 3 nucleotides fromthe antisense strand of a RNAi agent to KRAS selected from the specificduplexes provided herein and as listed, e.g., in Table 1.

In another embodiment, the present disclosure relates to such a method,wherein the composition comprising a RNAi agent further comprises asense strand, wherein the sense strand comprises at least 15 contiguousnucleotides differing by 0, 1, 2, or 3 nucleotides from the sense strandof a RNAi agent to KRAS selected from the specific duplexes providedherein and as listed, e.g., in Table 1.

In one embodiment of the method, the RNAi agent comprises at least ananti-sense strand, and/or comprises a sense and an anti-sense strand,wherein the sequence of the sense and/or anti-sense strand is thesequence of the sense and/or the anti-sense strand of a RNAi agent toKRAS selected from those specific duplex provided herein and as listed,e.g., in Table 1, wherein the composition further comprises apharmaceutically effective formulation.

In one embodiment of the method, the RNAi agent comprises at least ananti-sense strand, and/or comprises a sense and an anti-sense strand,wherein the sequence of the sense and/or anti-sense strand comprises thesequence of the sense and/or the anti-sense strand of a RNAi agent toKRAS selected from those specific duplex provided herein and as listed,e.g., in Table 1, wherein the composition further comprises apharmaceutically effective formulation.

Various particular specific embodiments of these embodiments aredescribed below.

In one embodiment, the KRAS-related disease is a proliferative disease,or cardio-facio-cutaneous (CFC) syndrome or Noonan syndrome.

In one embodiment, the KRAS-related disease is a proliferative disease,including without limitation a solid or liquid cancer, adenocarcinoma,colorectal cancer, advanced and/or metastatic colorectal cancer, coloncancer, lung, non-small cell lung cancer and lung adenocarcinoma, acutemyelogenous lung, bladder, brain, breast, cervical, endometrial,gastric, head and neck, kidney, leukemia, myelodysplastic syndrome,myeloid leukemia, liver, melanoma, ovarian, pancreatic, prostate,testicular, thyroid cancers, or cardio-facio-cutaneous (CFC) syndrome orNoonan syndrome.

In one embodiment, the method further comprises the administration of anadditional treatment. In one embodiment, the additional treatment is atherapeutically effective amount of a composition.

In one embodiment, the additional treatment is a method (or procedure).

In one embodiment, the additional treatment and the RNAi agent can beadministered in any order, or can be administered simultaneously.

In one embodiment, the method further comprises the step ofadministering an additional treatment for a proliferative disease,cardio-facio-cutaneous (CFC) syndrome or Noonan syndrome.

In one embodiment, the method further comprises the step ofadministering an additional treatment or therapy selected from the listof an additional antagonist to a KRAS-related disease.

In one embodiment, the composition comprises a second RNAi agent toKRAS. In various embodiments, the second RNAi agent is physicallyseparate from the first, or the two are physically connected (e.g.,covalently linked or otherwise conjugated).

In one embodiment, the method further comprises the step ofadministering an additional RNAi agent which comprises at least 15contiguous nucleotides differing by 0, 1, 2, or 3 nucleotides from theantisense strand of a RNAi agent to KRAS selected from the specificduplexes provided herein and as listed, e.g., in Table 1.

A Method of Inhibiting the Expression of KRAS Using a RNAi AgentDescribed Herein

In one particular specific embodiment, the present disclosure relates toa method of inhibiting the expression of KRAS in an individual,comprising the step of administering to the individual a therapeuticallyeffective amount of a composition comprising a RNAi agent of the presentdisclosure.

In one embodiment of the method, the RNAi agent comprises at least ananti-sense strand, and/or comprises a sense and an anti-sense strand,wherein the anti-sense strand comprises at least 15 contiguousnucleotides differing by 0, 1, 2, or 3 nucleotides from the anti-sensestrand of a RNAi agent to KRAS selected from those specific duplexprovided herein and as listed, e.g., in Table 1.

In one embodiment of the method, the RNAi agent comprises at least ananti-sense strand, and/or comprises a sense and an anti-sense strand,wherein the sequence of the sense and/or anti-sense strand is thesequence of the sense and/or the anti-sense strand of a RNAi agent toKRAS selected from those specific duplex provided herein and as listed,e.g., in Table 1, wherein the composition is in a pharmaceuticallyeffective formulation.

In one embodiment of the method, the RNAi agent comprises at least ananti-sense strand, and/or comprises a sense and an anti-sense strand,wherein the sequence of the sense and/or anti-sense strand comprises thesequence of the sense and/or the anti-sense strand of a RNAi agent toKRAS selected from those specific duplex provided herein and as listed,e.g., in Table 1, wherein the composition is in a pharmaceuticallyeffective formulation.

Various particular embodiments of these embodiments are described below.

In one embodiment, the individual is afflicted with or susceptible to aKRAS-related disease.

In one embodiment, the KRAS-related disease is a proliferative disease,or cardio-facio-cutaneous (CFC) syndrome or Noonan syndrome.

In one embodiment, the KRAS-related disease is a proliferative disease,including without limitation a solid or liquid cancer, e.g.,adenocarcinoma, colorectal cancer, advanced and/or metastatic colorectalcancer, colon cancer, lung, non-small cell lung cancer and lungadenocarcinoma, acute myelogenous lung, bladder, brain, breast,cervical, endometrial, gastric, head and neck, kidney, leukemia,myelodysplastic syndrome, myeloid leukemia, liver, melanoma, ovarian,pancreatic, prostate, testicular, thyroid cancers, orcardio-facio-cutaneous (CFC) syndrome or Noonan syndrome.

In one embodiment, the method further comprises the administration of anadditional treatment. In one embodiment, the additional treatment is atherapeutically effective amount of a composition. In one embodiment,the additional treatment is a therapeutically relevant method (orprocedure).

In one embodiment, the additional treatment and the RNAi agent can beadministered in any order or can be administered simultaneously.

In one embodiment, the method further comprises the step ofadministering an additional treatment for a proliferative disease,cardio-facio-cutaneous (CFC) syndrome or Noonan syndrome.

In one embodiment, the composition comprises a second RNAi agent toKRAS. In various embodiments, the second RNAi agent is physicallyseparate from the first, or the two are physically connected (e.g.,covalently linked or otherwise conjugated).

In one embodiment, the method further comprises the step ofadministering an additional RNAi agent which comprises at least 15contiguous nucleotides differing by 0, 1, 2, or 3 nucleotides from theantisense strand of a RNAi agent to KRAS selected from the specificduplexes provided herein and as listed, e.g., in Table 1.

Pharmaceutical Compositions of a RNAi Agent to KRAS

In one particular specific embodiment, the present disclosure relates toa composition comprising a RNAi agent of the present disclosure. In oneembodiment, the RNAi agent comprises at least an anti-sense strand,and/or comprises a sense and an anti-sense strand, wherein theanti-sense strand comprises at least 15 contiguous nucleotides differingby 0, 1, 2, or 3 nucleotides from the anti-sense strand of a RNAi agentto KRAS selected from those specific duplex provided herein and aslisted, e.g., in Table 1, wherein the composition is in apharmaceutically effective formulation.

In one embodiment, the RNAi agent comprises at least an anti-sensestrand, and/or comprises a sense and an anti-sense strand, wherein thesequence of the sense and/or anti-sense strand is the sequence of thesense and/or the anti-sense strand of a RNAi agent to KRAS selected fromthose specific duplex provided herein and as listed, e.g., in Table 1,wherein the composition is in a pharmaceutically effective formulation.

In one embodiment, the RNAi agent comprises at least an anti-sensestrand, and/or comprises a sense and an anti-sense strand, wherein thesequence of the sense and/or anti-sense strand comprises the sequence ofthe sense and/or the anti-sense strand of a RNAi agent to KRAS selectedfrom those specific duplex provided herein and as listed, e.g., in Table1, wherein the composition is in a pharmaceutically effectiveformulation.

In one embodiment, the present disclosure pertains to the use of a RNAiagent in the manufacture of a medicament for treatment of a KRAS-relateddisease, wherein the RNAi agent comprises a sense strand and anantisense strand, wherein the antisense strand comprises at least 15contiguous nucleotides differing by 0, 1, 2, or 3 nucleotides from theantisense strand of a RNAi agent to KRAS selected from those specificduplex provided herein and as listed, e.g., in Table 1.

Specific Embodiments of RNAi Agents to KRAS comprising mismatches fromthe disclosed sequences

Various specific embodiments of a RNAi agent to KRAS are disclosedherein. The present disclosure encompasses the example modifiedsequences provided in Tables 1 to 6, and the corresponding unmodifiedsequences and other modified sequences (e.g., modified and unmodifiedvariants). Specific embodiments of the present disclosure include RNAiagents which comprise sequences differing by 0, 1, 2, or 3 nt(nucleotides) or by [basepair(s)] (e.g., with 0, 1, 2 or 3 mismatches)from any of the RNAi agents listed in Table 1, and modified andunmodified variants thereof. As described in additional detail below, amismatch is defined herein as a difference between the base sequence(e.g., A instead of G) or length when two sequences are maximallyaligned and compared. In addition, as described in more detail below, an“unmodified variant” is a variant in which the base sequence isidentical, but none of the bases are modified; this includes, forexample, a sequence identical to the corresponding portion of thewild-type KRAS mRNA or gene. A “modified variant” contains one or moremodifications (or one or more fewer or different modifications) to anucleotide, sugar, phosphate or backbone, and/or addition of one or moremoieties; but without a change, substitution, addition, or deletion tothe base sequence. A particular sequence and its modified or unmodifiedvariants have 0 mismatches among them.

In one particular embodiment, the present disclosure comprises a RNAiagent comprising a sense and an anti-sense strand, wherein the senseand/or anti-sense strand comprises at least 15 contiguous nucleotidesdiffering by 0, 1, 2, or 3 nt from the sequence of the sense and/oranti-sense strand of: any of the RNAi agents listed in Tables 1 to 6,and modified and unmodified variants thereof.

In another particular embodiment, the RNAi agent comprises a sensestrand comprising at least 15 contiguous nucleotides differing by 0, 1,2, or 3 nt from the sense strand of any of the RNAi agents listed inTables 1 to 6, and modified and unmodified variants thereof.

OTHER EMBODIMENTS

Various particular specific embodiments of this disclosure are describedbelow.

In one embodiment, the disclosure pertains to a composition according toany of the embodiments described herein, for use in a method of treatinga KRAS-related disease in an individual, the method comprising the stepof administering to the individual a therapeutically effective amount ofa composition according to any of the claims.

One embodiment of the disclosure is the use of a composition accordingto any of these embodiments, in the manufacture of a medicament fortreatment of an KRAS-related disease.

In one embodiment, the KRAS-related disease is a proliferative disease,or cardio-facio-cutaneous (CFC) syndrome or Noonan syndrome.

In one embodiment, the KRAS-related disease is a proliferative disease,including without limitation a solid or liquid cancer, adenocarcinoma,colorectal cancer, advanced and/or metastatic colorectal cancer, coloncancer, lung, non-small cell lung cancer and lung adenocarcinoma, acutemyelogenous lung, bladder, brain, breast, cervical, endometrial,gastric, head and neck, kidney, leukemia, myelodysplastic syndrome,myeloid leukemia, liver, melanoma, ovarian, pancreatic, prostate,testicular, thyroid cancers, or cardio-facio-cutaneous (CFC) syndrome orNoonan syndrome.

In one embodiment, the disclosure pertains to the composition of any ofthe above embodiments, for use in the treatment of an KRAS-relateddisease.

DEFINITIONS

For convenience, the meaning of certain terms and phrases used in thespecification, examples, and appended claims, are provided below. Ifthere is an apparent discrepancy between the usage of a term in otherparts of this specification and its definition provided in this section,the definition in this section shall prevail.

KRAS

By “KRAS” is meant the gene, mRNA, and/or protein, or any nucleic acidencoding the protein, or any mutant, variant or modified versionthereof, designated by the Approved Gene Symbol: KRAS; Cytogeneticlocation: 12p 12.1; Genomic coordinates (GRCh37):12:25,358,179-25,403,853 (from NCBI), which also variously designated:KRas, K-ras, K-RAS, GTPase KRas, and V-Ki-ras2 Kirsten rat sarcoma viraloncogene homolog, C-K-RAS; K-RAS2A; K-RAS2B; K-RAS4A; K-RAS4B; KI-RAS;KRAS2; RASK2; v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog[Source: MGI Symbol; Acc: MGI: 96680]; OMIM: 190070 MGI: 96680HomoloGene: 37990 GeneCards: KRAS Gene; Species Human: Entrez 3845;Ensembl ENSG00000133703; UniProt P01116; RefSeq (mRNA) NM_(—)004985.3;RefSeq (protein) NP_(—)004976.2; Location (UCSC) Chr 12: 25.36-25.4 Mb;Species-Mouse: Entrez-16653; Ensembl-ENSMUSG00000030265; UniProt-070564;RefSeq (mRNA)-NM_(—)021284.6; RefSeq (protein)-NP_(—)067259.4; Location(UCSC)-Chr 6: 145.17-145.2 Mb.

The Ras Subfamily

The Ras subfamily (an abbreviation of RAt Sarcoma) is a proteinsubfamily of small GTPases that are involved in cellular signaltransduction and other processes. Activation of Ras signaling causescell growth, differentiation and survival.

Since Ras communicates signals from outside the cell to the nucleus,mutations in ras genes can cause permanent activation and inappropriatetransmission inside the cell, even in the absence of extracellularsignals. Because these signals result in cell growth and division,dysregulated or otherwise aberrant Ras signaling can ultimately lead tooncogenesis and cancer. Goodsell et al. 1999. Oncologist 4. 3: 263-4.Activating mutations in Ras are found in a third of all human tumors andup to 90% in specific tumor types. Downward. 2003. Nat. Rev. Cancer 3.1: 11-22; Bos et al. 1989 Cancer Res. 49: 4682-4689; and Forbes et al.2006 Br. J. Cancer 94: 318-322

The ras genes were first identified as the transforming oncogenes[Malumbres et al. 2003. Nat. Rev. Cancer 3. 6: 459-65] responsible forthe cancer-causing activities of the Harvey (the HRAS oncogene) andKirsten (KRAS) sarcoma viruses, by Scolnick and colleagues at theNational Institutes of Health (NIH). Chang et al. 1982. Proc. Natl.Acad. Sci. U.S.A. 79. 16: 4848-52. These viruses were discoveredoriginally in rats during the 1960s by Jennifer Harvey [Harvey. 1964.Nature 204. 4963: 1104-5] and Werner Kirsten [Kirsten et al. 1970. BiblHaematol. 36: 246-9], respectively. In 1982, activated and transforminghuman KRAS genes were discovered in human cancer cells [Santos et al.1982. Nature 298. 5872: 343-7], [Parada et al. 1982. Nature 297. 5866:474-8]. Subsequent studies identified a third human KRAS gene,designated NRAS, for its initial identification in human neuroblastomacells.

The three human KRAS genes encode highly related 188 to 189 amino acidproteins, designated H-Ras, N-Ras and K-Ras4A and K-Ras4B (the two K-Rasproteins arise from alternative gene splicing). For additionalinformation pertaining to KRAS cloning and isoforms, see, for example,Der et al. 1982 Proc. Nat. Acad. Sci. 79: 3637-3640; Chang et al. 1982Proc. Nat. Acad. Sci. 79: 4848-4852; McCoy et al. 1983 Nature 302:79-81; McGrath et al. 1983 Nature 304: 501-506; and Carta et al. 2006Am. J. Hum. Genet. 79: 129-135.

Ras Function

Ras proteins function as binary molecular switches that controlintracellular signaling networks. Ras-regulated signal pathways, controlsuch processes as actin cytoskeletal integrity, proliferation,differentiation, cell adhesion, apoptosis, and cell migration. Ras andras-related proteins are often deregulated in cancers, leading toincreased invasion and metastasis and decreased apoptosis.

Ras activates several pathways, of which the mitogen-activated protein(MAP) kinase cascade has been well-studied. This cascade transmitssignals downstream and results in the transcription of genes involved incell growth and division. There is a separate AKT pathway that inhibitsapoptosis.

In various embodiments, the RNAi agents can be used to treatKRAS-related diseases in which any one or more of these pathways orfunctions is altered. In various embodiments, the present disclosureencompasses KRAS RNAi agents that modulate or alter Ras-regulated signalpathways, including the MAP kinase cascade, and/or modulate or alterprocesses such as actin cytoskeletal integrity, proliferation,differentiation, cell adhesion, apoptosis, and cell migration. Ras andras-related proteins are often deregulated in cancers, leading toincreased invasion and metastasis and decreased apoptosis.

Activation and Deactivation

Ras is a G protein, or a guanosine-nucleotide-binding protein.Specifically, it is a single-subunit small GTPase, which is related instructure to the G_(α) subunit of heterotrimeric G proteins (largeGTPases). G proteins function as binary signaling switches with “on” and“off” states. In the “off” state it is bound to the nucleotide guanosinediphosphate (GDP), while in the “on” state, Ras is bound to guanosinetriphosphate (GTP), which has an extra phosphate group as compared toGDP. This extra phosphate holds the two switch regions in a“loaded-spring” configuration (specifically the Thr-35 and Gly-60). Whenreleased, the switch regions relax which causes a conformational changeinto the inactivate state. Hence, activation and deactivation of Ras andother small G proteins are controlled by cycling between the activeGTP-bound and inactive GDP-bound forms.

Critical regions of KRAS for oncogenic activity include codons 12, 13,59, 60, 61, 63 and 153. Grimmond et al. 1992 Urol. Res. 20:121-126;Burmer et al. 1989 Proc. Natl. Acad. Sci. 86: 2403-2407. Mutationssometimes appear affecting these codons. Some KRAS mutations cause RASto accumulate in the GTP-bound state by impairing intrinsic GTPaseactivity and conferring resistance to GTPase-activating proteins. Zenkeret al. 2007 J. Med. Genet. 44: 131-135. In various embodiments, thesequence of the KRAS RNAi agent encompasses the portion of the codingsegment corresponding to any of the above-listed codons. In variousembodiments, the KRAS RNAi agent has a mismatch to the wild-type (wt)KRAS sequence, such that the sequence of the KRAS RNAi agent matches thesequence of a mutated portion of the KRAS gene. In various embodiments,the disclosure encompasses the administration to a patient of a KRASRNAi agent with a sequence corresponding to that of a particularmutation found in the patient, optionally combined with theadministration of a KRAS RNAi agent with a sequence encompassing the wtsequence. In some embodiments, the KRAS RNAi agents correspond todifferent portions of the KRAS mRNA. In some embodiments, the patientmay have one or more mutations corresponding to particular codons ofKRAS (e.g., codons 12, 13 and/or 59), but the remainder of the KRAS geneis wild type, and thus the patient can be administered a KRAS RNAi agentwith a wild-type sequence which does not span the mutation, and/oradministered a KRAS RNAi agent with a sequence corresponding to the oneor more mutations.

In some embodiments, the disclosure encompasses a method involving thesteps of identifying a patient with a KRAS-related disease, isolating anucleic acid encoding or corresponding to the KRAS protein or gene fromthe patient, determining the sequence of the nucleic acid to determineif there is a mutation in the KRAS gene, and, if the sequence indicatesa mutation in KRAS, producing a KRAS RNAi agent with a sequence whichcorresponds to the mutation, and administering the KRAS RNAi agent in atherapeutically effective amount to treat or ameliorate the KRAS-relateddisease. In some embodiments, the KRAS RNAi agent is administered alongwith or as part of a treatment regimen with another disease treatmentappropriate to the KRAS-related disease.

The process of RAS exchanging the bound nucleotide is facilitated byguanine nucleotide exchange factors (GEFs) and GTPase activatingproteins (GAPs). As per its classification, Ras has an intrinsic GTPaseactivity, which means that the protein on its own will hydrolyze a boundGTP molecule into GDP. However this process is too slow for efficientfunction, and hence the GAP for Ras, RasGAP, may bind to and stabilizethe catalytic machinery of Ras, supplying additional catalytic residues(“arginine finger”) such that a water molecule is optimally positionedfor nucleophilic attack on the gamma-phosphate of GTP. An inorganicphosphate is released and the Ras molecule is now bound to a GDP. Sincethe GDP-bound form is “off” or “inactive” for signaling, GTPaseActivating Protein inactivates Ras by activating its GTPase activity.Thus, GAPs accelerate Ras inactivation.

GEFs catalyze a “push and pull” reaction which releases GDP from Ras.They insert close to the P-loop and magnesium cation binding site andinhibit the interaction of these with the gamma phosphate anion. Acidic(negative) residues in switch II “pull” a lysine in the P-loop away fromthe GDP, which “pushes” switch I away from the guanine. The contactsholding GDP in place are broken and it is released into the cytoplasm.Because intracellular GTP is abundant relative to GDP (approximately 10fold more). GTP predominantly re-enters the nucleotide binding pocket ofRas and reloads the spring. Thus GEFs facilitate Ras activation. Wellknown GEFs include Son of Sevenless (Sos) and cdc25 which include theRasGEF domain.

The balance between GEF and GAP activity determines the guaninenucleotide status of Ras, thereby regulating Ras activity.

In the GTP-bound conformation, Ras has high affinity for numerouseffectors which allow it to carry out its functions. These include PI3K.Other small GTPases may bind adaptors such as arfaptin or secondmessenger systems such as adenylyl cyclase. The Ras binding domain isfound in many effectors and invariably binds to one of the switchregions, because these change conformation between the active andinactive forms. However, they may also bind to the rest of the proteinsurface.

In various embodiments, the present disclosure encompasses KRAS RNAiagents that modulate the amount of KRAS and/or the amount of activatedKRAS in a cell. In various other embodiments, the present disclosureencompasses a composition or pharmaceutical composition comprisingand/or a method of treatment involving one or more KRAS RNAi agents anda second agent (e.g., another RNAi agent, antibody, or small molecule)which targets a factor which interacts with KRAS (e.g., PI3K, GAP,etc.).

Ras in Cancer

Mutations in the Ras family of proto-oncogenes are very common. Apharmacological approach that curtails Ras activity can inhibit certaincancer types. Ras point mutations are the single most common abnormalityof human proto-oncogenes. Pathologic Basis of Disease 8th ed. 2010. p.282. Ras inhibitor trans-farnesylthiosalicylic acid (FTS, Salirasib)exhibits profound anti-oncogenic effects in many cancer cell lines.Rotblat et al. 2008. Methods Enzymol 439: 467-89; and Blum et al. 2005.Cancer Research 65. 3: 999-1006.

In various embodiments, KRAS RNAi agents disclosed herein can beintroduced into tumor cells with a point mutation in KRAS or othermutation causing an over-expression or hyper-activity of KRAS. Suchcells are termed “KRAS-defective” cells.

Inappropriate activation of the gene has been shown to play a key rolein signal transduction, proliferation and malignant transformation.Lodish et al. 2000. Chapter 25. Cancer. Molecular cell biology. 4th ed.San Francisco: W.H. Freeman.

Mutations in a number of different genes as well as KRAS itself can alsohave this effect. Oncogenes such as p210BCR-ABL or the growth receptorerbB are upstream of Ras, so if they are constitutively activated theirsignals will transduce through Ras.

The tumour suppressor gene NF1 encodes a Ras-GAP—its mutation inneurofibromatosis will mean that Ras is less likely to be inactivated.RNAi agents targeting KRAS can thus be used in conjunction with otheragents (e.g., other RNAi agents) which target other factors which effectKRAS and its various pathways.

Finally, Ras oncogenes can be activated by point mutations so that theGTPase reaction can no longer be stimulated by GAP—this increases thehalf life of active Ras-GTP mutants.

In various embodiments, the KRAS RNAi agent can be administered topatients having a KRAS-related diseases involving a mutation outsideKRAS, such as in p210BCR-ABL, erbB, or NF1. In various otherembodiments, the present disclosure encompasses a composition orpharmaceutical composition or treatment method involving both one ormore KRAS RNAi agents and one or more agents (e.g., a RNAi agent,antibody or small molecule) which targets another factor which causesinappropriate activation of KRAS, such as in p210BCR-ABL, erbB, or NF1.

Constitutively Active Ras

Constitutively active Ras (Ras^(D)) is one which contains mutations thatprevent GTP hydrolysis, thus locking Ras in a permanently ‘On’ state.

The most common mutations are found at residue G12 in the P-loop and thecatalytic residue Q61.

The glycine to valine mutation at residue 12 renders the GTPase domainof Ras insensitive to inactivation by GAP and thus stuck in the “onstate”. Ras requires a GAP for inactivation as it is a relatively poorcatalyst on its own, as opposed to other G-domain-containing proteinssuch as the alpha subunit of heterotrimeric G proteins.

Residue 61 is responsible for stabilizing the transition state for GTPhydrolysis. Because enzyme catalysis in general is achieved by loweringthe energy barrier between substrate and product, mutation of Q61 to Knecessarily reduces the rate of intrinsic Ras GTP hydrolysis tophysiologically meaningless levels.

In various embodiments, the present disclosure pertains to a method oftreatment of a patient having or susceptible to a KRAS-related disease,wherein the KRAS is constitutively active.

KRAS Sequences in Various Species

The sequence of KRAS gene has determined for various species, includingHuman (HGNC: 6407; NM_(—)004985.3); Mouse (MGI:96680); and Rat(RGD:2981). A RNAi agent specific to KRAS can be designed such that thesequence thereof completely matches that of the mRNA corresponding tothe human KRAS gene and the homologous gene from a test animal. This isadvantageous when developing a therapeutic RNAi agent since the sameRNAi agent can be used in both a test animal (e.g., rat, mouse, orcynomolgus monkey, etc.) and a human.

The KRAS sequence in cynomolgus monkey (Macaca fascicularis, or “cyno”)has been partially determined. Shown below are the partial cyno sequenceand comparisons beween portions of the cyno and human KRAS sequences.NM_(—)004985 KRAS, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homologconsensus—target length=5312, consensus length=4474, 23 contigs (longestis 775) 113 mismatches, 1651.87410068346 reads, coverage: max=96,mean=13.158; consensus consistency=99.41%, target/consensus conservation97.47%.

KRAS Cynomolgus Sequence:

[SEQ ID NO: 1709] NNNNNNNNNN NNNNNNNNNN NNNNNNNNNN NNNNNNNNNN NNNNNNNNNNNNNNNNNNNN 60 NNNNNNNNNN NNNNNNNNNN NNNNNNNNNN NNNNNNNNNN NNNNNNNNNNNNAGGCACTG 120 AAGGCGGCGG CGGGGCCAGA GGCTCAGCGG CTCCCCGGGG CGGGAGAGAGNNNNNNNNNN 180 NNNNNNNNNN NNNNNNNNNN NNNNAGTTGG AGCTGGTGGG GTAGGCAAGAGTGCCTTGAC 240 NNNNNNGCTA ATTCAGAATC ATTTTGTGGA CGAATATGAT CCAACAATAGAGGATTCCTA 300 CAGGAAGCAA GTAGTAATTG ATGGAGAAAC CTGTCTCTTG GATATTCTCGACACAGCAGG 360 TCAAGAGGAG TACAGTGCAA TGAGGGACCA GTACATGAGG ACTGGGGAGGGCTTTCTTTG 420 TGTATTTGCC ATAAATAATA CTAAATCATT TGAAGATATT CACCATTATAGAGAACAAAT 480 TAAAAGAGTT AAGGACTCTG AAGATGTACC TATGGTCCTA GTAGGAAATAAATGTGATTT 540 GCCTTCTAGA ACAGTAGACA CAAAACAGGC TCAGGACTTA GCAAGAAGTTACGGAATTCC 600 TTTTATTGAA ACATCAGCAA AGACAAGACA GGGTGTTGAT GATGCCTTCTATACATTAGT 660 TCGAGAAATT CGAAAACATA AAGAAAAGAT GAGCAAAGAT GGTAAAAAGAAGAAAAAGAA 720 GTCAAAGACA AAGTGTGTAA TTATGTAAAT ACAATTTGTA CTTTTTTCTTAAGGCATACT 780 AGTAAAAGTG GTAATTTTTG TACATTACAC TAAATTATTA GCATTTGTTTTAGCATTACC 840 TAATTTTTTT CCTGCTCCAT GCAGACTGTT AGCTTTTACC TTAAATGCTTATTTTAAAAT 900 GACAGTGGAA GCTTTTTTTT CCTCTAAGTG CCAGTATTCC CAGAGTTTTGATTTTTGAAC 960 TAGCAATGCC TGTGAAAAAG AAACTGAATA CCTAAGATTT CTGTCTTGGGGTTTTTGGTG 1020 CNNNNNNNNN NNNNNNNNNN NNNNNNNNNN NNNNNNNNNN NNNNNNNNNNNNNNNNAATT 1080 AATGAAGCTT CTGAATCATC CCTATTCTGT GTTTTATCTA GTCACATAAATGGATTAATT 1140 ACTAATTTCA GTTGAGACCT TCTAATTGGT TTTTACTGAA ACATTGAGGGAACACAAANN 1200 NNNNNNNNNN NNNNNNNNNN NNNNTCTAGG CATCATGTCC TATAGTTTGTCATCCCTGAT 1260 GAATGTAAAG TTACACTGTT CACAAAGGTT TTGTTCCCTT TCCACTGCTATTAGTCATGG 1320 TCACTCTCCC CGNNNNNNNN NNNNNNNNNN NNNNNNNNNN NNNNNTGGAAAAAAATTACA 1380 AGTCAATGGA AACTATTATA AGGCCGTTTC CTTTTCACAT TAGATAAATTACTATAAAGA 1440 CTCCTAATAG CTTTTCCTGT TAAGGCAGAC CCAGTATGAA ATGGGGATTNNNNNNNNNNN 1500 NNNNNNNNNN NNNNNNNNNN NNNNNNNNNA ATTTTTATAA TAATTGAAATAATTTTAACA 1560 TGTATAAAAA ATTCTCATAG GAATTAAATG TAGTCTCCCT GTGTCAGATTGCTCTTTCAT 1620 AGTATAACTT TAAATCTTTT CTTCAACTTC AGTCTTTGAA GGTAGTTTTAATTCTGCTTG 1680 TGACATTAAA AGATTATTTG GGCCAGTTAT AGCTTAGTAG GTGTTGAAGAGACCAAGGTT 1740 GCATGGCCAG GCCCTGTGTG AACCTTTGAG CTTTCATAGA GAGTTTCACAGCATGGACTG 1800 TGTCCCCATG GTCATCCAGT GTTGTCATGC ATTGGTTAGT CAAAATGGGGAGGGACTAGG 1860 ACAGTTTGGA TAGGTCAACA AGATACATTC TCACTCTGTG GTGGTCCTGCTGACAAATCA 1920 AGAGCATTGC TTTTGTTTTT TAAGAAAATG AACTCTTTTT TAAAAATTACTTTTAAATAT 1980 TAACTCAAAA GTTGAGATTT TGGGGGGGTG GTATGCCAAG ACATTAATTTTTTTNNNNNN 2040 NNNNNNNNNN NNNAAGTTTT ACAATCTCTA GGTTTGGCTA GTTCTCTTAACACTGGTTAA 2100 ATTAACATTT CATAAACACT TTTCAAGNNN NNNNNNNNNN NNNNNNNNNNNNNNNNNNNN 2160 NNNNNNNNNN NNNNNNNNNN NNNATTTAAA ATGTTACTTA TTTTAAAATATATGAAATGA 2220 GATGGCATGG TGAGGTGAAA GTATCACTGG ACTANNAAGA AGGTGACTTAGGTTCTAGAT 2280 AGTTGTCTTT TAGGACTCTG ATTTTGAGGA CATCACTTAC TATCCATTTCTTCATGTTAA 2340 NNNNNNNNNN NNNNNNNNNN NNNNNNNNNN TTTTTACAAC TATGTGATTTATATTCCGTT 2400 TACATGAGGA TACACTTATT TGTCAAGCTC AGCACAATCT AAAAATTTTTAACCTATGTT 2460 ACACCATCTT CAGTGCCAAT CTTGGGCAAA ATTGTGCAAG AGGTGAAGTTTATATTTGAA 2520 TATCCATTCT CGTTTTAGGA CTCTCCTTCC ATGTTAGTGT CATCTTGCCTGCCTACCTTC 2580 CACATGCCCC ATGACTTGAT GCAGTTTTAA TACTTCTAAT TCCCCTAACCATAAGATTTA 2640 CTGCTGCTAT GGATATCTCC ATGAAGTTTT CCCNNNNNNN NNNNNNNNNNNNNNNNNNNN 2700 NNNNNNNNNN NNNNNNNNNN NGAGAATCTG ACAGATACCA TAATGGGATTTGACCTAATC 2760 ACTAATTTTC AGGTGGTGGC CGATCCTTTG AAAATATCTC TGCTGCCCAATCCATTAGCG 2820 ACAGTAGGAT TTTTCAGACC TGGTATGAAT AGACAGAACC CTATCCAGTGGAAGGAGAAT 2880 TTAATAAAGA TAGTACTGAA ATAATTCCTA AGGTAATCTA CAACTAGGACTACTCCTGGT 2940 AACAGTAATA CATTCCATTG TTTTAGTAAC CAGAAATNNN NNNNNNNNNNNNNNNNNNNN 3000 NNNNNNNNNN NNNNNNNNNN NNNNNNNNNN NNNNNNNNNN NNNNNNNNNNNNCCAGGCTG 3060 GAATGCAGTG GCGCCATCTC AGCTCACTGC AACCTCCATC TCCCAGGTTCAAGCGATTCT 3120 CGTGCCTCGG CATCCTGAGT AGCTGGGATT ACAGGCATGT GCCNCCACACTCAACTAATT 3180 TTTGTAGTTT TAGGAGAGAC AGGGTTTCAC CCTATTGGCC AGGCTGGTCTCGAACTCCTG 3240 ACCTCAAGTG ATTCACCCAC CTNNNCCTCA TAAAGCCGTT TTGCAGAACTCATTTATTCA 3300 GCAAATATTT ATTGAGTGCC TACCAGATGC CAGTCATTTC ACAAGGCACTGGGTATATGG 3360 TATCCCCAAA CAAGAGACAT AATCCTGGTC CTTAGCTAGT GCTAGCNNNNNNNNNNNNNN 3420 NNNNNNNNNN NNNNNNNNNN NNNNNNNNNN NNNNNNNNNN NNNNNNNNNNNNNNNNNNNN 3480 NNNNGGGGTT TGGTCCCTGT GCCTGCTCTA TAATTGTTTT GCTATGATTCCAGTGAAANN 3540 NNNNNNNNNN NNNNNNNNNN NNNNNNNNNN NNNNNNNNNN NNNNNNNNNNNNNNNNNNNN 3600 NNNNNNNNNN NNNNNNNNNN NNNNNNNNNN NNNNNNNNNN NNTTACTGTACACATTAAGG 3660 TGTATGTCAG ATATCCATAT TGAANNNNNN NNNNNNNNNN NNNNNNNNNNNNNNNNNNAT 3720 AATTAAAATA TACTTAAAAA TTAATAGTTT TATCTGGGTA CAAACAAACAGGTGCCTGAA 3780 CTAGTTCACA GACAAGGAAA CTTCTATGTA AAAATCAGTA TGATTTNNNNNNNNNNNNGT 3840 GAAACTACAG ATCTTTGGAA CATTGTTTAG ATAGGGTGTT AAGACTTACACAGTACCACG 3900 TTTCTACACA CAGAAAGAAA TGGCCATACT TCAGGAACTG CAGTGCTAATGAGGGGATAT 3960 TTAGGCCTCT TGAATTTTTG ATGTAGATGG GCATTTTTTT AAGGTANNTGGTAATTACCT 4020 TTATGTGAAC TTTGAATGGT TTAACAAAAG ATTTGTTTTT GTAGAGATTTTAAAGGGGGA 4080 GAATGCTAGA AATAAATGTT ATCTAANNNN NNNCGCCTTA AAGATAAAAATCCTTGTTGA 4140 AGTTTTTTAA AAAAAAGCTA AATTACATAG TCTTAGGCAT TAACATGTTTGTGGAAGAAT 4200 ATAGCACACA TATATTGTAT CATTTGAGTG AATATTCCCA AATAGGCATTCTAGGCTCTA 4260 TTTAACTGAG TCACACTGCA TAGGAATTTA GAACCTAACT TTTATAGGTTATCAAAACTG 4320 TTGCCTCCAT TGCACAATTT TGTCCTAATA CATACATGGA GACTTTGTGGGGCATGTTAA 4380 GTTACAGTTT GCACAAGTTC ATCTCATTTG TATTCCATTG ATTTTTTTTTTCTTCTAAAC 4440 ATTTTTTCTT CAAACAGTAT ATAACTTTTT TTAGGGGATT TTTTTTNNNNNNNNNNNNNN 4500 NNTCTGACGA TTTCCATTTG TCAAAAAGTA ATGATTTCTT GATAATTATGTAGTAATGTT 4560 TTTAAGAACC CAGCAGTTAC CTTAAAGCTG AATTTATATT TAATAACTTCTGTGTTAATA 4620 CTGGATAGCA TGAATTCTGC ATTGAGAAAC TGAATAGNNN NNNNNNNNNNNNNNNNNNNN 4680 NNNNNNNNNN NNNNNNNNCA TGAGTTCTTG AAGAATAGTC ATAACTAGATTAAGATCTGT 4740 GTTTTAGTTT AATAGTTTGA AGTGCCTGTT TGGGATAATG ATAGGTAATTTAGATGAATT 4800 TAGGGGGAAA AAAAGTTATC TGCAGAAATG TTGAGGGCCC ATCTCTCCCCACACACCCAC 4860 ATAGAGCTAA CTGGGTTACA GTGTTTTATC CGAAAGTTTC CAATTCCACTGTCTTGTGTT 4920 TTCATGTTGA AAATACTTTT GCATTTTTCC TTTGAGTGCC AATTTCTTACTAGTACTATT 4980 TCTTAATGTA ACATGTTTAC CTGGAATGTA TTTTAACTAT TTTTGTATAGTGTAAACTGA 5040 AACATGCACA TTTTGTACAT TGTGCTTTCT TTTGTGGGAC ATATGCAGTGTGATCCAGTT 5100 GTTTTCCATC ATTTGGTTGC GCTGACCTAG GAATGTTGGT CATATCAAACATTAAAAATG 5160 ACCACTCTTT TAATTGAAAT TAACTTTTAA ATGTTTATAG GAGTATGTGCTGTGAAGTGA 5220 TCTAAAATTT GTAATATTTT TGTCATGAAC TGTACTACTC CTAATTATTGTAATGTAATA 5280 AAAATAGTTA CAGTGACAAA AAAAAAAANN NN. 5312

Comparisons between portions of the human sequence and the cyno sequenceare presented below.

Human 113 AGGCACTGAAGGCGGCGGCGGGGCCAGAGGCTCAGCGGCTCCCAGGTGCGGGAGAGAGGC172 ||||||||||||||||||||||||||||||||||||||||||| || ||||||||||| Cyno 113AGGCACTGAAGGCGGCGGCGGGGCCAGAGGCTCAGCGGCTCCCCGGGGCGGGAGAGAGNN 172 Human173 CTGCTGAAAATGACTGAATATAAACTTGTGGTAGTTGGAGCTGGTGGCGTAGGCAAGAGT 232                          ||||||||||||||| |||||||||||| Cyno 173NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNAGTTGGAGCTGGTGGGGTAGGCAAGAGT 232 Human233 GCCTTGACGATACAGCTAATTCAGAATCATTTTGTGGACGAATATGATCCAACAATAGAG 292||||||||      |||||||||||||||||||||||||||||||||||||||||||||| Cyno 233GCCTTGACNNNNNNGCTAATTCAGAATCATTTTGTGGACGAATATGATCCAACAATAGAG 292 Human293 GATTCCTACAGGAAGCAAGTAGTAATTGATGGAGAAACCTGTCTCTTGGATATTCTCGAC 352|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 293GATTCCTACAGGAAGCAAGTAGTAATTGATGGAGAAACCTGTCTCTTGGATATTCTCGAC 352 Human353 ACAGCAGGTCAAGAGGAGTACAGTGCAATGAGGGACCAGTACATGAGGACTGGGGAGGGC 412|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 353ACAGCAGGTCAAGAGGAGTACAGTGCAATGAGGGACCAGTACATGAGGACTGGGGAGGGC 412 Human413 TTTCTTTGTGTATTTGCCATAAATAATACTAAATCATTTGAAGATATTCACCATTATAGA 472|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 413TTTCTTTGTGTATTTGCCATAAATAATACTAAATCATTTGAAGATATTCACCATTATAGA 472 Human473 GAACAAATTAAAAGAGTTAAGGACTCTGAAGATGTACCTATGGTCCTAGTAGGAAATAAA 532|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 473GAACAAATTAAAAGAGTTAAGGACTCTGAAGATGTACCTATGGTCCTAGTAGGAAATAAA 532 Human533 TGTGATTTGCCTTCTAGAACAGTAGACACAAAACAGGCTCAGGACTTAGCAAGAAGTTAT 592||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 533TGTGATTTGCCTTCTAGAACAGTAGACACAAAACAGGCTCAGGACTTAGCAAGAAGTTAC 592 Human593 GGAATTCCTTTTATTGAAACATCAGCAAAGACAAGACAGGGTGTTGATGATGCCTTCTAT 652|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 593GGAATTCCTTTTATTGAAACATCAGCAAAGACAAGACAGGGTGTTGATGATGCCTTCTAT 652 Human653 ACATTAGTTCGagaaattcgaaaacataaagaaaagatgagcaaagatggtaaaaagaaG 712|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 653ACATTAGTTCGAGAAATTCGAAAACATAAAGAAAAGATGAGCAAAGATGGTAAAAAGAAG 712 Human713 aaaaagaagtcaaagacaaagTGTGTAATTATGTAAATACAATTTGTACTTTTTTCTTAA 772|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 713AAAAAGAAGTCAAAGACAAAGTGTGTAATTATGTAAATACAATTTGTACTTTTTTCTTAA 772 Human773 GGCATACTAGTACAAGTGGTAATTTTTGTACATTACACTAAATTATTAGCATTTGTTTTA 832|||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||| Cyno 773GGCATACTAGTAAAAGTGGTAATTTTTGTACATTACACTAAATTATTAGCATTTGTTTTA 832 Human833 GCATTACCTAAtttttttCCTGCTCCATGCAGACTGTTAGCTTTTACCTTAAATGCTTAT 892|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 833GCATTACCTAATTTTTTTCCTGCTCCATGCAGACTGTTAGCTTTTACCTTAAATGCTTAT 892 Human893 TTTAAAATGACAGTGGAAGtttttttttCCTCTAAGTGCCAGTATTCCCAGAGTTTTGGT 952||||||||||||||||||| |||||||||||||||||||||||||||||||||||||| | Cyno 893TTTAAAATGACAGTGGAAGCTTTTTTTTCCTCTAAGTGCCAGTATTCCCAGAGTTTTGAT 952 Human953 TTTTGAACTAGCAATGCCTGTGAAAAAGAAACTGAATACCTAAGATTTCTGTCTTGGGGT 1012|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 953TTTTGAACTAGCAATGCCTGTGAAAAAGAAACTGAATACCTAAGATTTCTGTCTTGGGGT 1012 Human1013 TTTTGGTGCATGCAGTTGATTACTTCTTATTTTTCTTACCAATTGTGAATGTTGGTGTGA 1072||||||||| Cyno 1013TTTTGGTGCNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN 1072 Human1073 AACAAATTAATGAAGCTTTTGAATCATCCCTATTCTGTGTTTTATCTAGTCACATAAATG 1132    |||||||||||||| ||||||||||||||||||||||||||||||||||||||||| Cyno 1073NNNNAATTAATGAAGCTTCTGAATCATCCCTATTCTGTGTTTTATCTAGTCACATAAATG 1132 Human1133 GATTAATTACTAATTTCAGTTGAGACCTTCTAATTGGTTTTTACTGAAACATTGAGGGAA 1192|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 1133GATTAATTACTAATTTCAGTTGAGACCTTCTAATTGGTTTTTACTGAAACATTGAGGGAA 1192 Human1193 CACAAATTTATGGGCTTCCTGATGATGATTCTTCTAGGCATCATGTCCTATAGTTTGTCA 1252||||||                      |||||||||||||||||||||||||||| Cyno 1193CACAAANNNNNNNNNNNNNNNNNNNNNNNNNNTCTAGGCATCATGTCCTATAGTTTGTCA 1252 Human1253 TCCCTGATGAATGTAAAGTTACACTGTTCACAAAGGTTTTGTCTCCTTTCCACTGCTATT 1312||||||||||||||||||||||||||||||||||||||||||  |||||||||||||||| Cyno 1253TCCCTGATGAATGTAAAGTTACACTGTTCACAAAGGTTTTGTTCCCTTTCCACTGCTATT 1312 Human1313 AGTCATGGTCACTCTCCCCAAAATATTATATTTTTTCTATaaaaagaaaaaaatggaaaA 1372|||||||||||||||||||                              ||||||| Cyno 1313AGTCATGGTCACTCTCCCCGNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNTGGAAAA 1372 Human1373 aaaTTACAAGGCAATGGAAACTATTATAAGGCCATTTCCTTTTCACATTAGATAAATTAC 1432|||||||||| |||||||||||||||||||||| |||||||||||||||||||||||||| Cyno 1373AAATTACAAGTCAATGGAAACTATTATAAGGCCGTTTCCTTTTCACATTAGATAAATTAC 1432 Human1433 TATAAAGACTCCTAATAGCTTTTCCTGTTAAGGCAGACCCAGTATGAAATGGGGATTATT 1492||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 1433TATAAAGACTCCTAATAGCTTTTCCTGTTAAGGCAGACCCAGTATGAAATGGGGATTNNN 1492 Human1493 ATAGCAACCATTTTGGGGCTATATTTACATGCTACTAAATTTTTATAATAATTGAAAAGA 1552                              ||||||||||||||||||||  | Cyno 1493NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNAATTTTTATAATAATTGAAATAA 1552 Human1553 TTTTAACAAGTATAAAAAATTCTCATAGGAATTAAATGTAGTCTCCCTGTGTCAGACTGC 1612|||||||| ||||||||||||||||||||||||||||||||||||||||||||||| ||| Cyno 1553TTTTAACATGTATAAAAAATTCTCATAGGAATTAAATGTAGTCTCCCTGTGTCAGATTGC 1612 Human1613 TCTTTCATAGTATAACTTTAAATCTTTTCTTCAACTTGAGTCTTTGAAGATAGTTTTAAT 1672||||||||||||||||||||||||||||||||||||| ||||||||||| |||||||||| Cyno 1613TCTTTCATAGTATAACTTTAAATCTTTTCTTCAACTTCAGTCTTTGAAGGTAGTTTTAAT 1672 Human1673 TCTGCTTGTGACATTAAAAGATTATTTGGGCCAGTTATAGCTTATTAGGTGTTGAAGAGA 1732|||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||| Cyno 1673TCTGCTTGTGACATTAAAAGATTATTTGGGCCAGTTATAGCTTAGTAGGTGTTGAAGAGA 1732 Human1733 CCAAGGTTGCAAGGCCAGGCCCTGTGTGAACCTTTGAGCTTTCATAGAGAGTTTCACAGC 1792||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||| Cyno 1733CCAAGGTTGCATGGCCAGGCCCTGTGTGAACCTTTGAGCTTTCATAGAGAGTTTCACAGC 1792 Human1793 ATGGACTGTGTCCCCACGGTCATCCAGTGTTGTCATGCATTGGTTAGTCAAAATGGGGAG 1852|||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||| Cyno 1793ATGGACTGTGTCCCCATGGTCATCCAGTGTTGTCATGCATTGGTTAGTCAAAATGGGGAG 1852 Human1853 GGACTAGGGCAGTTTGGATAGCTCAACAAGATACAATCTCACTCTGTGGTGGTCCTGCTG 1912|||||||| |||||||||||| ||||||||||||| |||||||||||||||||||||||| Cyno 1853GGACTAGGACAGTTTGGATAGGTCAACAAGATACATTCTCACTCTGTGGTGGTCCTGCTG 1912 Human1913 ACAAATCAAGAGCATTGCTTTTGTTTCTTAAGAAAACAAACTCTTTTTTAAAAATTACTT 1972|||||||||||||||||||||||||| |||||||||  |||||||||||||||||||||| Cyno 1913ACAAATCAAGAGCATTGCTTTTGTTTTTTAAGAAAATGAACTCTTTTTTAAAAATTACTT 1972 Human1973 TTAAATATTAACTCAAAAGTTGAGATTTTGGGGTGGTGGTGTGCCAAGACATTAAttttT 2032||||||||||||||||||||||||||||||||| |||||| ||||||||||||||||||| Cyno 1973TTAAATATTAACTCAAAAGTTGAGATTTTGGGGGGGTGGTATGCCAAGACATTAATTTTT 2032 Human2033 tttttAAACAATGAAGTGAAAAAGTTTTACAATCTCTAGGTTTGGCTAGTTCTCTTAACA 2092||                 ||||||||||||||||||||||||||||||||||||||| Cyno 2033TTNNNNNNNNNNNNNNNNNNNAAGTTTTACAATCTCTAGGTTTGGCTAGTTCTCTTAACA 2092 Human2093 CTGGTTAAATTAACATTGCATAAACACTTTTCAAG 2127 [SEQ ID NO: 1710]||||||||||||||||| ||||||||||||||||| Cyno 2093CTGGTTAAATTAACATTTCATAAACACTTTTCAAG 2127 [SEQ ID NO: 1711] Human 2184atttaaaatgttacttattttaaaataaatGAAGTGAGATGGCATGGTGAGGTGAAAGTA 2243||||||||||||||||||||||||||| ||||| |||||||||||||||||||||||||| Cyno 2184ATTTAAAATGTTACTTATTTTAAAATATATGAAATGAGATGGCATGGTGAGGTGAAAGTA 2243 Human2244 TCACTGGACTAGGAAGAAGGTGACTTAGGTTCTAGATAGGTGTCTTTTAGGACTCTGATT 2303|||||||||||  |||||||||||||||||||||||||| |||||||||||||||||||| Cyno 2244TCACTGGACTANNAAGAAGGTGACTTAGGTTCTAGATAGTTGTCTTTTAGGACTCTGATT 2303 Human2304 TTGAGGACATCACTTACTATCCATTTCTTCATGTTAAAAGAAGTCATCTCAAACTCTTAG 2363||||||||||||||||||||||||||||||||||||| Cyno 2304TTGAGGACATCACTTACTATCCATTTCTTCATGTTAANNNNNNNNNNNNNNNNNNNNNNN 2363 Human2364 ttttttttttttACAACTATGTAATTTATATTCCATTTACATAAGGATACACTTATTTGT 2423       ||||||||||||||| ||||||||||| ||||||| ||||||||||||||||| Cyno 2364NNNNNNNTTTTTACAACTATGTGATTTATATTCCGTTTACATGAGGATACACTTATTTGT 2423 Human2424 CAAGCTCAGCACAATCTGTAAATTTTTAACCTATGTTACACCATCTTCAGTGCCAGTCTT 2483|||||||||||||||||  |||||||||||||||||||||||||||||||||||| |||| Cyno 2424CAAGCTCAGCACAATCTAAAAATTTTTAACCTATGTTACACCATCTTCAGTGCCAATCTT 2483 Human2484 GGGCAAAATTGTGCAAGAGGTGAAGTTTATATTTGAATATCCATTCTCGTTTTAGGACTC 2543|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 2484GGGCAAAATTGTGCAAGAGGTGAAGTTTATATTTGAATATCCATTCTCGTTTTAGGACTC 2543 Human2544 TTCTTCCATATTAGTGTCATCTTGCCTCCCTACCTTCCACATGCCCCATGACTTGATGCA 2603| ||||||| ||||||||||||||||| |||||||||||||||||||||||||||||||| Cyno 2544TCCTTCCATGTTAGTGTCATCTTGCCTGCCTACCTTCCACATGCCCCATGACTTGATGCA 2603 Human2604 GTTTTAATACTTGTAATTCCCCTAACCATAAGATTTACTGCTGCTGTGGATATCTCCATG 2663|||||||||||| |||||||||||||||||||||||||||||||| |||||||||||||| Cyno 2604GTTTTAATACTTCTAATTCCCCTAACCATAAGATTTACTGCTGCTATGGATATCTCCATG 2663 Human2664 AAGTTTTCCCACTGAGTCACATCAGAAATGCCCTACATCTTATTTCCTCAGGGCTCAAGA 2723||||||||||                                          || Cyno 2664AAGTTTTCCCNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNGA 2723 Human2724 GAATCTGACAGATACCATAAAGGGATTTGACCTAATCACTAATTTTCAGGTGGTGGCTGA 2783|||||||||||||||||||| |||||||||||||||||||||||||||||||||||| || Cyno 2724GAATCTGACAGATACCATAATGGGATTTGACCTAATCACTAATTTTCAGGTGGTGGCCGA 2783 Human2784 TGCTTTGAACATCTCTTTGCTGCCCAATCCATTAGCGACAGTAGGATTTTTCAAACCTGG 2843| ||||||| || ||| |||||||||||||||||||||||||||||||||||| |||||| Cyno 2784TCCTTTGAAAATATCTCTGCTGCCCAATCCATTAGCGACAGTAGGATTTTTCAGACCTGG 2843 Human2844 TATGAATAGACAGAACCCTATCCAGTGGAAGGAGAATTTAATAAAGATAGTGCTGAAAGA 2903||||||||||||||||||||||||||||||||||||||||||||||||||| |||||| | Cyno 2844TATGAATAGACAGAACCCTATCCAGTGGAAGGAGAATTTAATAAAGATAGTACTGAAATA 2903 Human2904 ATTCCTTAGGTAATCTATAACTAGGACTACTCCTGGTAACAGTAATACATTCCATTGTTT 2963|||||| |||||||||| |||||||||||||||||||||||||||||||||||||||||| Cyno 2904ATTCCTAAGGTAATCTACAACTAGGACTACTCCTGGTAACAGTAATACATTCCATTGTTT 2963 Human2964 TAGTAACCAGAAAT 2977 [SEQ ID NO: 1712] |||||||||||||| Cyno 2964TAGTAACCAGAAAT 2977 [SEQ ID NO: 1713] Human 3053CCAGGCTGGAATGCAGTGGCGCCATCTCAGCTCACTGCAACCTCCATCTCCCAGGTTCAA 3112|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 3053CCAGGCTGGAATGCAGTGGCGCCATCTCAGCTCACTGCAACCTCCATCTCCCAGGTTCAA 3112 Human3113 GCGATTCTCGTGCCTCGGCCTCCTGAGTAGCTGGGATTACAGGCGTGTGCCACTACACTC 3172||||||||||||||||||| |||||||||||||||||||||||| |||||| | |||||| Cyno 3113GCGATTCTCGTGCCTCGGCATCCTGAGTAGCTGGGATTACAGGCATGTGCCNCCACACTC 3172 Human3173 AACTAATTTTTGTATTTTTAGGAGAGACGGGGTTTCACCCTGTTGGCCAGGCTGGTCTCG 3232|||||||||||||| ||||||||||||| |||||||||||| |||||||||||||||||| Cyno 3173AACTAATTTTTGTAGTTTTAGGAGAGACAGGGTTTCACCCTATTGGCCAGGCTGGTCTCG 3232 Human3233 AACTCCTGACCTCAAGTGATTCACCCACCTTGGCCTCATAAACCTGTTTTGCAGAACTCA 3292||||||||||||||||||||||||||||||   ||||||||| | ||||||||||||||| Cyno 3233AACTCCTGACCTCAAGTGATTCACCCACCTNNNCCTCATAAAGCCGTTTTGCAGAACTCA 3292 Human3293 TTTATTCAGCAAATATTTATTGAGTGCCTACCAGATGCCAGTCACCGCACAAGGCACTGG 3352||||||||||||||||||||||||||||||||||||||||||||   ||||||||||||| Cyno 3293TTTATTCAGCAAATATTTATTGAGTGCCTACCAGATGCCAGTCATTTCACAAGGCACTGG 3352 Human3353 GTATATGGTATCCCCAAACAAGAGACATAATCCCGGTCCTTAGGTAGTGCTAG 3405||||||||||||||||||||||||||||||||| ||||||||| ||||||||| Cyno 3353GTATATGGTATCCCCAAACAAGAGACATAATCCTGGTCCTTAGCTAGTGCTAG 3405 Human 3643TTACTGTACACATTAAGGTGTATGTCAGATATTCATATTGACCCAAATGTGTAATATTCC 3702|||||||||||||||||||||||||||||||| |||||||| Cyno 3643TTACTGTACACATTAAGGTGTATGTCAGATATCCATATTGAANNNNNNNNNNNNNNNNNN 3702 Human3703 AGTTTTCTCTGCATAAGTAATTAAAATATACTTAAAAATTAATAGTTTTATCTGGGTACA 3762               ||||||||||||||||||||||||||||||||||||||||||| Cyno 3703NNNNNNNNNNNNNNNNATAATTAAAATATACTTAAAAATTAATAGTTTTATCTGGGTACA 3762 Human3763 AATAAACAGGTGCCTGAACTAGTTCACAGACAAGGAAACTTCTATGTAAAAATCACTATG 3822|| |||||||||||||||||||||||||||||||||||||||||||||||||||| |||| Cyno 3763AACAAACAGGTGCCTGAACTAGTTCACAGACAAGGAAACTTCTATGTAAAAATCAGTATG 3822 Human3823 ATTTCTGAATTGCTATGTGAAACTACAGATCTTTGGAACACTGTTTAGGTAGGGTGTTAA 3882||||         |||||||||||||||||||||||| ||||||| ||||||||||| Cyno 3823ATTTNNNNNNNNNNNNGTGAAACTACAGATCTTTGGAACATTGTTTAGATAGGGTGTTAA 3882 Human3883 GACTTACACAGTACCTCGTTTCTACACAGAGAAAGAAATGGCCATACTTCAGGAACTGCA 3942||||||||||||||| |||||||||||| ||||||||||||||||||||||||||||||| Cyno 3883GACTTACACAGTACCACGTTTCTACACACAGAAAGAAATGGCCATACTTCAGGAACTGCA 3942 Human3943 GTGCTTATGAGGGGATATTTAGGCCTCTTGAATTTTTGATGTAGATGGGCAtttttttAA 4002||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 3943GTGCTAATGAGGGGATATTTAGGCCTCTTGAATTTTTGATGTAGATGGGCATTTTTTTAA 4002 Human4003 GGTAGTGGTTAATTACCTTTATGTGAACTTTGAATGGTTTAACAAAAGATTTGTTTTTGT 4062||||   | ||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 4003GGTANNTGGTAATTACCTTTATGTGAACTTTGAATGGTTTAACAAAAGATTTGTTTTTGT 4062 Human4063 AGAGATTTTAAAGGGGGAGAATTCTAGAAATAAATGTTACCTAATTATTACAGCCTTAAA 4122|||||||||||||||||||||| |||||||||||||||| ||||        |||||||| Cyno 4063AGAGATTTTAAAGGGGGAGAATGCTAGAAATAAATGTTATCTAANNNNNNNCGCCTTAAA 4122 Human4123 GACAAAAATCCTTGTTGAAGtttttttaaaaaaaGCTAAATTACATAGACTTAGGCATTA 4182|| ||||||||||||||||||||||| ||||||||||||||||||||| ||||||||||| Cyno 4123GATAAAAATCCTTGTTGAAGTTTTTTAAAAAAAAGCTAAATTACATAGTCTTAGGCATTA 4182 Human4183 ACATGTTTGTGGAAGAATATAGCAGACGTATATTGTATCATTTGAGTGAATGTTCCCAAG 4242|||||||||||||||||||||||| || ||||||||||||||||||||||| ||||||| Cyno 4183ACATGTTTGTGGAAGAATATAGCACACATATATTGTATCATTTGAGTGAATATTCCCAAA 4242 Human4243 TAGGCATTCTAGGCTCTATTTAACTGAGTCACACTGCATAGGAATTTAGAACCTAACTTT 4302|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 4243TAGGCATTCTAGGCTCTATTTAACTGAGTCACACTGCATAGGAATTTAGAACCTAACTTT 4302 Human4303 TATAGGTTATCAAAACTGTTGTCACCATTGCACAATTTTGTCCTAATATATACATAGAAA 4362||||||||||||||||||||| | |||||||||||||||||||||||| |||||| || | Cyno 4303TATAGGTTATCAAAACTGTTGCCTCCATTGCACAATTTTGTCCTAATACATACATGGAGA 4362 Human4363 CTTTGTGGGGCATGTTAAGTTACAGTTTGCACAAGTTCATCTCATTTGTATTCCATTGAT 4422|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 4363CTTTGTGGGGCATGTTAAGTTACAGTTTGCACAAGTTCATCTCATTTGTATTCCATTGAT 4422 Human4423 tttttttttcttctaaacattttttcttcaaacagtatataactttttttaggggatttT 4482|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 4423TTTTTTTTTCTTCTAAACATTTTTTCTTCAAACAGTATATAACTTTTTTTAGGGGATTTT 4482 Human4483 tttttAGACAGCAAAAACTATCTGAAGATTTCCATTTGTCAAAAAGTAATGATTTCTTGA 4542||||              ||||| |||||||||||||||||||||||||||||||||| Cyno 4483TTTTNNNNNNNNNNNNNNNNTCTGACGATTTCCATTTGTCAAAAAGTAATGATTTCTTGA 4542 Human4543 TAATTGTGTAGTAATGTTTTTTAGAACCCAGCAGTTACCTTAAAGCTGAATTTATATTTA 4602||||| ||||||||||||||| |||||||||||||||||||||||||||||||||||||| Cyno 4543TAATTATGTAGTAATGTTTTTAAGAACCCAGCAGTTACCTTAAAGCTGAATTTATATTTA 4602 Human4603 GTAACTTCTGTGTTAATACTGGATAGCATGAATTCTGCATTGAGAAACTGAATAGCTGTC 4662 |||||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 4603ATAACTTCTGTGTTAATACTGGATAGCATGAATTCTGCATTGAGAAACTGAATAGNNNNN 4662 Human4663 ATAAAATGAAACTTTCTTTCTAAAGAAAGATACTCACATGAGTTCTTGAAGAATAGTCAT 4722                             |||||||||||||||||||||||| Cyno 4663NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNCATGAGTTCTTGAAGAATAGTCAT 4722 Human4723 AACTAGATTAAGATCTGTGTTTTAGTTTAATAGTTTGAAGTGCCTGTTTGGGATAATGAT 4782|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 4723AACTAGATTAAGATCTGTGTTTTAGTTTAATAGTTTGAAGTGCCTGTTTGGGATAATGAT 4782 Human4783 AGGTAATTTAGATGAATTTAGGGGaaaaaaaaGTTATCTGCAGATATGTTGAGGGCCCAT 4842|||||||||||||||||||||||| ||||||||||||||||||| ||||||||||||||| Cyno 4783AGGTAATTTAGATGAATTTAGGGGGAAAAAAAGTTATCTGCAGAAATGTTGAGGGCCCAT 4842 Human4843 CTCTCCCCCCACACCCCCACAGAGCTAACTGGGTTACAGTGTTTTATCCGAAAGTTTCCA 4902|||||||| ||||||| || |||||||||||||||||||||||||||||||||||||||| Cyno 4843CTCTCCCCACACACCCACATAGAGCTAACTGGGTTACAGTGTTTTATCCGAAAGTTTCCA 4902 Human4903 ATTCCACTGTCTTGTGTTTTCATGTTGAAAATACTTTTGCATTTTTCCTTTGAGTGCCAA 4962|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 4903ATTCCACTGTCTTGTGTTTTCATGTTGAAAATACTTTTGCATTTTTCCTTTGAGTGCCAA 4962 Human4963 TTTCTTACTAGTACTATTTCTTAATGTAACATGTTTACCTGGAATGTATTTTAACTATTT 5022|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 4963TTTCTTACTAGTACTATTTCTTAATGTAACATGTTTACCTGGAATGTATTTTAACTATTT 5022 Human5023 TTGTATAGTGTAAACTGAAACATGCACATTTTGTACATTGTGCTTTCTTTTGTGGGACAT 5082|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 5023TTGTATAGTGTAAACTGAAACATGCACATTTTGTACATTGTGCTTTCTTTTGTGGGACAT 5082 Human5083 ATGCAGTGTGATCCAGTTGTTTTCCATCATTTGGTTGCGCTGACCTAGGAATGTTGGTCA 5142|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 5083ATGCAGTGTGATCCAGTTGTTTTCCATCATTTGGTTGCGCTGACCTAGGAATGTTGGTCA 5142 Human5143 TATCAAACATTAAAAATGACCACTCTTTTAATTGAAATTAACTTTTAAATGTTTATAGGA 5202|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 5143TATCAAACATTAAAAATGACCACTCTTTTAATTGAAATTAACTTTTAAATGTTTATAGGA 5202 Human5203 GTATGTGCTGTGAAGTGATCTAAAATTTGTAATATTTTTGTCATGAACTGTACTACTCCT 5262|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Cyno 5203GTATGTGCTGTGAAGTGATCTAAAATTTGTAATATTTTTGTCATGAACTGTACTACTCCT 5262 Human5263 AATTATTGTAATGTAATAAAAATAGTTACAGTGACaaaaaaaaaaA 5308|||||||||||||||||||||||||||||||||||||||||||||| Cyno 5263AATTATTGTAATGTAATAAAAATAGTTACAGTGACAAAAAAAAAAA 5308 Human [SEQ ID NO:1714] Cyno [SEQ ID NO: 1715]

The lowercase letters in the KRAS sequence are an NCBI convention forlow-complexity sequences. The matching algorithm frequently excludesthese when calculating match scores, as they tend to match against largenumbers of things in the genome.

In one embodiment, the KRAS RNAi agent of the present disclosurecomprises a sequence which is identical in the all three of human, ratand cyno KRAS mRNAs. This sequence identity across species facilitatesanimal testing prior to human testing, since the sequence of the RNAidoes not need to be modified due to species-specific differences in thetarget sequence. In one embodiment, the KRAS RNAi agent comprises asequence which is identical in the human, mouse and cyno KRAS mRNAs. Invarious embodiments, the KRAS RNAi agent comprises a sequence which isidentical in human and mouse, human and rat, and/or human and cyno.

Additional Embodiments of a RNAi Agent to KRAS

The present disclosure pertains to RNAi agents which target human KRAS.In one embodiment, the KRAS RNAi agent comprises a sequence which doesnot match that of any other mRNA or gene. In one embodiment, the KRASRNAi agent comprises a sequence which differs from all other knownnon-KRAS mRNAs or genes by at least 0, 1, 2 or 3 nucleotides. Anincrease in the number of mismatches between the KRAS RNAi sequence andthat of any other gene can decrease the amount of “off-target effects”or the RNAi agent targeting a non-target gene (e.g., a gene that is notKRAS).

In one embodiment, the KRAS RNAi agent of the present disclosure isadministered to a patient in need thereof (e.g., a patient sufferingfrom a KRAS-related disease).

The patient can also be administered more than one RNAi agent specificto KRAS. In one embodiment, the KRAS RNAi agent(s) of the presentdisclosure can optionally be administered along with one or moreadditional pharmaceutical agent appropriate for that disease. In oneembodiment, the KRAS RNAi agent(s) of the present disclosure can beoptionally administered along with any other appropriate additionaltreatment, wherein the additional treatment can be a composition (e.g.,another agent that can treat a KRAS-related disease such as a cancertreatment) or a method (e.g., surgery to remove a tumor if theKRAS-related disease is a cancer).

The RNAi agent(s) and additional disease treatment(s) can beadministered in any order, simultaneously, concurrently, separately, orsequentially, or in one or multiple doses over time.

Additional Definitions

For convenience, the meaning of certain terms and phrases used in thespecification, examples, and appended claims, are provided below. Ifthere is an apparent discrepancy between the usage of a term in otherparts of this specification and its definition provided in this section,the definition in this section shall prevail.

As used throughout this disclosure, articles such as “a” and “an” referto one or more than one (at least one) of the grammatical object of thearticle.

RNAi Agent

In one embodiment, the present disclosure pertains to a KRAS RNAi agentor other composition comprising at least an antisense nucleic acidsequence complementary to a KRAS nucleic acid (or portion thereof), orpertains to a recombinant expression vector encoding an shRNA orcomposition comprising the antisense nucleic acid that can function asan RNAi as defined below. As used herein, an “antisense” nucleic acidcomprises a nucleotide sequence complementary to a “sense” nucleic acidencoding the KRAS protein (e.g., complementary to the coding strand of adouble-stranded DNA, complementary to an mRNA or complementary to thecoding strand of a KRAS gene or nucleic acid).

RNAi agents include, as non-limiting examples, siRNAs (small interferingRNAs), dsRNAs (double stranded RNAs), shRNAs (short hairpin RNAs) andmiRNAs (micro RNAs).

In various embodiments, the present disclosure pertains to any RNAiagent comprising a RNA sequence corresponding to any DNA sequencesdisclosed herein (e.g., wherein the DNA nucleotides are replaced by thecorresponding RNA nucleotide, for example, with T in DNA replaced by Uin RNA, and with ribose instead of deoxyribose in the sugar-phosphatebackbone).

In one embodiment, the RNAi comprises a single strand. Thissingle-stranded RNAi agent oligonucleotide or polynucleotide cancomprise the sense or antisense strand, as described by Sioud 2005 J.Mol. Biol. 348:1079-1090, and references therein. Thus the disclosureencompasses RNAi agents with a single strand comprising either the senseor antisense strand of an RNAi agent described herein. The disclosurealso encompasses RNAi agents comprising a single strand, wherein thesingle strand comprises the sequences of both the antisense and sensestrands of any RNAi agent disclosed herein, e.g., wherein the strandsare contiguous, connected by a loop or otherwise linked. Examples ofsuch molecules include those with a hairpin between the sense andanti-sense sequences (e.g., shRNA).

The RNAi agent(s) of the present disclosure target (e.g., bind to,anneal to, hybridize, etc.) the KRAS mRNA. The use of the RNAi agentspecific to KRAS results in a decrease of KRAS activity, level and/orexpression, e.g., a “knock-down” (KD) or “knock-out” of the target geneor target sequence. In one embodiment, in the case of a disease statecharacterized by over-expression or hyper-activity of KRAS,administration of a RNAi agent to KRAS knocks down the KRAS targetenough to provide a more normal or therapeutic level of KRAS activity orexpression.

In one embodiment, the RNAi comprises a single strand (such as an shRNA,as described herein).

In various embodiments, one or both strands contain one or more nicks,i.e., a break or missing bond in the phosphate backbone, such that atleast one nucleotide subunit is not covalently linked to the adjacentnucleotide subunit in any given sequence. In some embodiments, thepassenger strand is nicked (see, for example, WO 2007/107162). Invarious embodiments, one or both strands contain one or more gaps, e.g.,wherein at least one entire nucleotide subunit is absent from thedisclosed sequence. Where a sense or antisense sequence contains a gap,that strand is envisioned to comprise two separate oligonucleotides.

Particularly useful siRNAs include those which can bind specifically tothose regions of the KRAS mRNA that have one or more of the followingqualities: binding in the coding segment of KRAS; binding at or near thejunction of the 5′ untranslated region and the start of the codingsegment; binding at or near the translational start site of the mRNA;binding at, across or near junctions of exons and introns; little or nobinding to the mRNAs or transcripts of other genes (little or no“off-target effects”); binding to the KRAS mRNA in or near a region orregions that is not double-stranded or a stem region, e.g., those in aloop or single-stranded portion; eliciting little or no immunogenicity;binding in a segment of the KRAS mRNA sequence which is conserved amongvarious animal species (including human, mouse, rat, cyno, etc.), as thepresence of a conserved sequence facilitates testing using variouslaboratory animals; binding to double-stranded region(s) of the mRNA;binding to an AT-rich region (e.g., at least about 50, 51, 52, 53, 54,55, 56, 57, 58, 59, or 60% AT-rich); and/or lacking particular sequencesknown or suspected to decrease siRNA activity, e.g., the presence of aGG sequence at the 5′ end, which may decrease separation of thedouble-stranded portion of the siRNA. In one embodiment, the RNAi agentspecific to KRAS can be a double-stranded RNA having any one or more ofthese qualities.

The term “double-stranded RNA” or “dsRNA,” as used herein, refers to aRNAi agent comprising a first and a second strand; e.g., a compositionthat includes an RNA molecule or complex of molecules having ahybridized duplex region (i.e., a region where the nucleotide bases fromthe first strand and the second strand are paired) that comprises twoanti-parallel and substantially complementary nucleic acid strands,which will be referred to as having “sense” and “antisense” orientationswith respect to a target RNA. The antisense strand, with respect to themRNA target, is also called the “guide” strand, and the sense strand isalso called the “passenger” or “anti-guide” strand. The passenger strandcan include at least one or more of the following: one or more extranucleotides (e.g., a bulge or 1 nt loop) compared to the other strand, anick, a gap, a mismatch, etc., compared to the other strand. In variousembodiments, the RNAi agent comprises a first strand and a secondstrand. In various embodiments, and as used herein and as is clear bycontext, terminology referring to the first strand refers to the sensestrand and the second strand refers to the anti-sense strand as listedin any Table herein. In other embodiments, and as used herein and as isclear by context, the first strand refers to the anti-sense strand, andthe second strand refers to the sense strand as listed in any Tableherein.

The duplex region can be of any length that permits specific degradationof a desired target RNA through a RISC pathway, but will typically rangefrom 9 to 36 base pairs (“bp”) in length, e.g., 15-30 bp in length.Considering a duplex between 9 and 36 bp, the duplex can be any lengthin this range, for example, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 bpand any sub-range therebetween, including, but not limited to 15-30 bp,15-26 bp, 15-23 bp, 15-22 bp, 15-21 bp, 15-20 bp, 15-19 bp, 15-18 bp,15-17 bp, 18-30 bp, 18-26 bp, 18-23 bp, 18-22 bp, 18-21 bp, 18-20 bp,19-30 bp, 19-26 bp, 19-23 bp, 19-22 bp, 19-21 bp, 19-20 bp, 19 bp, 20-30bp, 20-26 bp, 20-25 bp, 20-24 bp, 20-23 bp, 20-22 bp, 20-21 bp, 20basepairs, 21-30 bp, 21-26 bp, 21-25 bp, 21-24 bp, 21-23 bp, 21-22 bp,21 bp, 22 bp, or 23 bp. The dsRNAs generated in the cell by processingwith Dicer and similar enzymes are generally in the range of about 19 toabout 22 bp in length. One strand of the duplex region of a dsRNAcomprises a sequence that is substantially complementary to a region ofa target RNA. The two strands forming the duplex structure can be from asingle RNA molecule having at least one self-complementary duplexregion, or can be formed from two or more separate RNA molecules thathybridize to form the duplex. Where the duplex region is formed from twoself-complementary regions of a single molecule, the molecule can have aduplex region separated by a single-stranded chain of nucleotides(herein referred to as a “hairpin loop”, e.g., such as found in an shRNAconstruct) between the 3′-end of one strand and the 5′-end of therespective other strand forming the duplex structure. The hairpin loopcan comprise at least one unpaired nucleotide; in some embodiments thehairpin loop can comprise at least 3, at least 4, at least 5, at least6, at least 7, at least 8, at least 9, at least 10, at least 20, atleast 23 or more unpaired nucleotides. Where the two substantiallycomplementary strands of a dsRNA are comprised by separate RNAmolecules, those molecules need not, but can, be covalently connected.Where the two strands are connected covalently by a hairpin loop, theconstruct is generally referred to herein and in the art as a “shRNA”.Where the two strands are connected covalently by means other than ahairpin loop, the connecting structure is referred to as a “linker.”

RNAi Agents to KRAS Comprising Mismatches from the Disclosed Sequences

Various specific embodiments of a RNAi agent to KRAS are disclosedherein; example sequences are provided in Tables 1, 2 and 3. Specificembodiments of the present disclosure include RNAi agents which comprisesequences differing by 0, 1, 2, or 3 nt (nucleotides) or by[basepair(s)] (e.g., with 0, 1, 2 or 3 mismatches) from any of the RNAiagents listed in Tables 1 to 6, and modified and unmodified variantsthereof.

A mismatch is defined herein as a difference between the base sequenceor length when two sequences are maximally aligned and compared. Amismatch is defined as a position wherein the base of one sequence doesnot match the base of the other sequence. Thus, a mismatch is counted,for example, if a position in one sequence has a particular base (e.g.,A), and the corresponding position on the other sequence has a differentbase (e.g., G). Substitution of A, for example, with T, C, G or U wouldconstitute a mismatch. Substitution of G with T, A, C or U would alsoconstitute a mismatch. Substitution of C with T, G, A or U would alsoconstitute a mismatch. Substitution of U with A, C or G would constitutea mismatch. Note, however, that on a given strand, a U can be replacedby T (either as RNA or, preferably, DNA, e.g., 2′-deoxy-thymidine); thereplacement of a U with a T is not a mismatch as used herein, as eitherU or T can pair with A on the opposite strand. The RNAi agent can thuscomprise one or more DNA bases, e.g., T. In some cases, in a portion orportions of the RNAi agent, DNA can be used in place of RNA (e.g., inthe seed region), to form a DNA-RNA hybrid. See, for example, Yamato etal. 2011 cancer Gene Ther. 18: 587-597. No mismatch is counted between aDNA portion(s) of the RNAi agent and the corresponding target mRNA ifbasepairing occurs (e.g., between A, G, C, or T in the DNA portion, andthe corresponding U, C, G, or A, respectively in the mRNA).

A mismatch is also counted, e.g., if a position in one sequence has abase (e.g., A), and the corresponding position on the other sequence hasno base (e.g., that position is an abasic nucleotide, which comprises aphosphate-sugar backbone but no base). A single-stranded nick in eithersequence (or in the sense or anti-sense strand) is not counted asmismatch. Thus, as a non-limiting example, no mismatch would be countedif one sequence comprises the sequence AG, but the other sequencecomprises the sequence AG with a single-stranded nick between the A andthe G. A nucleotide modification in the sugar or phosphate is also notconsidered a mismatch. Thus, if one sequence comprises a C, and theother sequence comprises a modified C (e.g., 2′-modification) at thesame position, no mismatch would be counted.

Thus, no mismatches are counted if modifications are made to the sugar,phosphate, or backbone of the RNAi agent without modifying the base.Thus, a sequence of GGACGAAUAUGAUCCAACA (SEQ ID NO: 1) as an RNA and thesame sequence as a PNA (peptide nucleic acid) (or TNA or GNA or FANA)have 0 mismatches from each other.

It is also noted that the sequences of the RNAi agents in Tables 1 to 6include sequences which comprise modifications, as detailed in Table 3.It is noted that dTdT (2′-deoxy-thymidine-5′-phosphate and2′-deoxy-thymidine-5′-phosphate), or in some cases, TT or UU, is addedas a cap or extension to both 3′-ends, but this cap or extension is notincluded in the calculation of the total number of mismatches. Inaddition, in Table 3, a modified sequence can comprise one or moremodifications from the corresponding unmodified sequence. In this case,lowercase “c” represents 2′-O-methylcytidine-5′-phosphate, and lowercase“u” represents 2′-O-methyluridine-5′-phosphate. Uppercase “A”, “C”, “G”and “U” represent the un-modified adenosine-5′-phosphate,cytidine-5′-phosphate, guanosine-5′-phosphate, and uridine-5′-phosphate,respectively. The substitution of modified c for unmodified C does notcount as a mismatch in numbering the 0, 1, 2, or 3 mismatches betweensequences. This nomenclature is used for all sequences in Tables 1 to 6.Thus, an equal number of mismatches would be calculated (a) between atest sequence and a modified sequence, and (b) between the same testsequence and the corresponding unmodified sequence from the KRAS gene,and (c) between a modified sequence and a differently modified sequencewhich have the same base sequence.

In one particular embodiment, the present disclosure comprises a RNAiagent comprising a anti-sense strand comprising at least 15 to 19contiguous nucleotides differing by 0, 1, 2, or 3 nt from the sequenceof the anti-sense strand of: any of the RNAi agents listed in Tables 1to 6, and modified and unmodified variants thereof.

The present disclosure pertains to “modified and unmodified variants” ofthe disclosed sequences.

An “unmodified variant” of a particular sequence is the correspondingportion of KRAS without any modifications. Example modified sequencesare listed in Tables 1, 2 and 3. The “unmodified variants” of thesequences of Tables 1 to 6 have the identical sequence, without basemodifications or terminal dTdT. A given sequence and an “unmodifiedvariant” of it differ by 0 nt (and have no mismatches).

A “modified variant” of a particular sequence comprises one or more (orone or more fewer) modifications to the backbone, sugar, phosphate orbase, but do not have any base substitutions (e.g., G for C, or A forG); thus a given sequence and a modified variant thereof differ by 0 nt(and have no mismatches). As another example, a given sequence as a RNAand the same sequence as a PNA are modified variants of each other anddiffer by 0 nt (and have no mismatches). Similarly, the same sequence(with no base substitutions) as a locked nucleic acid (LNA), Morpholino,threose nucleic acid (TNA), or glycol nucleic acid (GNA) would be amodified variant which has 0 mismatches.

As detailed below, substituting a single nucleotide at a given positionwith a modified version of the same nucleotide would produce a modifiedvariant (with 0 mismatches).

In another particular embodiment, the RNAi agent comprises a sensestrand comprising at least 15 contiguous nucleotides differing by 0, 1,2, or 3 nt from the sense strand of any of the RNAi agents listed inTables 1 to band modified and unmodified variants thereof.

RNAi agents to KRAS of the present disclosure can be used in RNAinterference.

Modifications of RNAi Agent Sequences

The present disclosure encompasses both unmodified sequences and examplemodified sequences, such as those disclosed in Tables 1, 2 and 3.

The present disclosure further encompasses any other modification of adisclosed sequence (e.g., a modified variant).

For example, the disclosure encompasses a RNAi agent with a substitutionof a single nucleotide at a given position with a modified version ofthe same nucleotide. Thus a nucleotide (A, G, C or U) can be replaced bythe corresponding 5-fluorouracil, 5-bromouracil, 5-chlorouracil,5-iodouracil, hypoxanthine, xantine, 4-acetylcytosine,5-(carboxyhydroxylmethyl) uracil,5-carboxymethylaminomethyl-2-thiouridine,5-carboxymethylaminomethyluracil, dihydrouracil,beta-D-galactosylqueosine, inosine, N6-isopentenyladenine,1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine,2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine,7-methylguanine, 5-methylaminomethyluracil,5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine,5′-methoxycarboxymethyluracil, 5-methoxyuracil,2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v),wybutoxosine, pseudouracil, queosine, 2-thiocytosine,5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil,uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v),5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3) w,or 2,6-diaminopurine.

Additional modified variants include the addition of any other moiety(e.g., a radiolabel or other tag or conjugate) to the RNAi agent;provided that the base sequence is identical, the addition of othermoieties produces a “modified variant” (with no mismatches).

Various sets of modifications can be used. These include the followingformats, which are used in various screens disclosed herein.

A22S26

A22 indicates that All UA as 2′-OMe-U A and all CA as 2′-OMe-C AS26 indicates that All U as 2′-OMe-U and all C as 2′-OMe-CAll 3′ overhangs as 2′-OMe-U 2′-OMe-U

In addition to these modifications and patterns (e.g, formats) formodifications, other modifications or sets of modifications of thesequences provided can be generated using common knowledge of nucleicacid modification.

RNA Interference

RNA interference (RNAi) is a post-transcriptional, targetedgene-silencing technique that uses double-stranded RNA (dsRNA) todegrade messenger RNA (mRNA) containing the same sequence as the dsRNA.The process of RNAi occurs when ribonuclease III (Dicer) cleaves thelonger dsRNA into shorter fragments called siRNAs. siRNAs (smallinterfering RNAs) produced by Dicer are typically about 21 to 23nucleotides long and comprise about 19 base pair duplexes (thoughartificial siRNAs or RNAi agents can be shorter or longer, and/orblunt-ended, and/or comprises one or more endcaps). The smaller RNAsegments then mediate the degradation of the target mRNA. Dicer has alsobeen implicated in the excision of 21- and 22-nucleotide small temporalRNAs (stRNAs) from precursor RNA of conserved structure that areimplicated in translational control. Hutvagner et al. 2001 Science 293:834. The RNAi response also features an endonuclease complex, commonlyreferred to as an RNA-induced silencing complex (RISC), which mediatescleavage of single-stranded mRNA complementary to the anti-sense strandof the RNAi agent. Cleavage of the target RNA takes place in the middleof the region complementary to the anti-sense strand of the siRNAduplex.

In one aspect, an RNA interference agent includes a single-stranded RNAthat interacts with a target RNA sequence to direct the cleavage of thetarget RNA. Without wishing to be bound by theory, the presentdisclosure contemplates a long double-stranded RNA introduced intoplants and invertebrate cells is broken down into siRNA by a Type IIIendonuclease known as Dicer. Sharp et al. 2001 Genes Dev. 15:485. Dicer,a ribonuclease-III-like enzyme, processes the dsRNA into 19-23 base pairshort interfering RNAs with characteristic two base 3′ overhangs.Bernstein, et al. 2001 Nature 409:363. The siRNAs are then incorporatedinto an RNA-induced silencing complex (RISC) where one or more helicasesunwind the siRNA duplex, enabling one of the now unpaired siRNA strandsto act as a “guide” strand to guide target recognition. Nykanen, et al.2001 Cell 107:309. Upon binding of the antisense guide strand to theappropriate target mRNA, one or more endonucleases within the RISCcleaves the target to induce silencing. Elbashir, et al. 2001 Genes Dev.15:188. Thus, in one aspect the present disclosure relates to asingle-stranded RNA that promotes the formation of a RISC complex toeffect silencing of the target gene.

Kits for RNAi synthesis are commercially available, e.g., from NewEngland Biolabs and Ambion.

The RNAi agent(s) of the present disclosure target (e.g., bind to,anneal to, etc.) the KRAS mRNA. The use of the RNAi agent to KRASresults in a decrease of KRAS activity, level and/or expression, e.g., a“knock-down” or “knock-out” of the target gene or target sequence.Particularly, in one embodiment, in the case of a disease statecharacterized by over-expression or hyper-activity of KRAS,administration of a RNAi agent to KRAS knocks down the KRAS targetenough to restore a normal level of KRAS activity.

A suitable RNAi agent can be selected by any process known in the art orconceivable by one of ordinary skill in the art. For example, theselection criteria can include one or more of the following steps:initial analysis of the KRAS gene sequence and design of RNAi agents;this design can take into consideration sequence similarity acrossspecies (human, cynomolgus, mouse, etc.) and dissimilarity to other(non-KRAS) genes; screening of RNAi agents in vitro (e.g., at 10 nM inRKO cells); determination of EC50 in RKO cells; determination ofviability of cells treated with RNAi agents, including insensitive cellswhich do not require KRAS for survival, or sensitive cells, which dorequire KRAS for survival; testing with human PBMC (peripheral bloodmononuclear cells), e.g., to test levels of TNF-alpha to estimateimmunogenicity, wherein immunostimulatory sequences are less desired;testing in human whole blood assay, wherein fresh human blood is treatedwith an RNAi agent and cytokine/chemokine levels are determined [e.g.,TNF-alpha (tumor necrosis factor-alpha) and/or MCP1 (monocytechemotactic protein 1)], wherein Immunostimulatory sequences are lessdesired; determination of gene knockdown in vivo using subcutaneoustumors in test animals; KRAS target gene modulation analysis, e.g.,using a pharmacodynamic (PD) marker, for example, other factors whoseexpression is affected by KRAS, wherein KRAS knockdown leads to adose-dependent reduction of abundance of those components; andoptimization of specific modifications of the RNAi agents.

The dsRNA molecules (RNAi agents) described herein are thus useful inRNA interference of KRAS.

Features of a RNAi Agent: Sense Strand, Antisense Strand and (Optional)Overhangs

In various embodiments, the RNAi agents comprise a first strand and asecond strand, e.g., a sense strand and an antisense strand (or anantisense and a sense strand) and, optionally, one or both ends of theduplex containing unpaired nucleotides referred to herein as overhangs.

The term “antisense strand” refers to the strand of a RNAi agent whichincludes a region that is substantially complementary to a targetsequence. As used herein, the term “region of complementarity” refers tothe region on the antisense strand that is substantially complementaryto a sequence, for example a target sequence, as defined herein. Wherethe region of complementarity is not fully complementary to the targetsequence, the mismatches may be in the internal or terminal regions ofthe molecule. Generally, the most tolerated mismatches are in theterminal regions, e.g., within 5, 4, 3, or 2 nucleotides of the 5′and/or 3′ terminus.

The term “sense strand,” as used herein, refers to the strand of a RNAiagent that includes a region that is substantially complementary to aregion of the antisense strand as that term is defined herein.

The sequence of a gene may vary from individual to individual,especially at wobble positions within the coding segment, or in theuntranslated region; individuals may also differ from each other incoding sequence, resulting in additional differences in mRNA. Thesequence of the sense and antisense strands of the RNAi agent can thusbe designed to correspond to that of an individual patient, if and whereneeded. RNAi agents can also be modified in sequence to reduceimmunogenicity, binding to undesired mRNAs (e.g., “off-target effects”)or to increase stability in the blood. These sequence variants areindependent of chemical modification of the bases or 5′ or 3′ or otherend-caps of the RNAi agents.

The RNAi agents can also have overhangs of 0, 1, or 2 overhangs; in thecase of a 0 nt overhang, they are blunt-ended. A RNAi agent can have 0,1 or 2 blunt ends. In a “blunt-ended RNAi agent” both strands terminatein a base-pair; thus a blunt-ended molecule lacks either 3′ or 5′single-stranded nucleotide overhangs.

The RNAi agents can comprise overhang(s), blunt end(s), and/or 5′ and 3′endcap(s).

As used herein, the term “overhang” or “nucleotide overhang” refer to atleast one unpaired nucleotide that protrudes from the end of at leastone of the two strands of the duplex structure of a RNAi agent. Forexample, when a 3′-end of one strand of a dsRNA extends beyond the5′-end of the other strand, or vice versa, the unpaired nucleotide(s)form the overhang. A dsRNA can comprise an overhang of at least onenucleotide; alternatively the overhang can comprise at least twonucleotides, at least three nucleotides, at least four nucleotides, atleast five nucleotides or more. An overhang can comprise or consist of anucleotide/nucleoside analog, including a deoxynucleotide/nucleoside.The overhang(s) may be on the sense strand, the antisense strand or anycombination thereof. Furthermore, the nucleotide(s) of an overhang canbe present on the 5′ end, 3′ end or both ends of either an antisense orsense strand of a dsRNA. The RNAi agent can also optionally comprise acap. The term “Cap” and the like include a chemical moiety attached tothe end of a double-stranded nucleotide duplex, but is used herein toexclude a chemical moiety that is a nucleotide or nucleoside. A “3′ Cap”is attached at the 3′ end of a nucleotide or oligonucleotide andprotects the molecule from degradation, e.g., from nucleases, such asthose in blood serum or intestinal fluid. A 3′ cap can replace a TT orUU dinucleotide at the end of a blunt-ended RNAi agent. In oneembodiment, 3′ end caps are as disclosed in, for example, WO 2005/021749and WO 2007/128477. A “5′ cap” is attached at the 5′ end of a nucleotideor oligonucleotide. A cap should not interfere (or unduly interfere)with RNAi activity.

The present disclosure thus contemplates a RNAi agent specific to KRAScomprising an antisense strand (which may be contiguous or connected viaa linker or loop) in a RNAi agent. In a more specific embodiment, anRNAi agent comprises an antisense strand and a sense strand whichtogether comprise a double-stranded or complementary region. In oneembodiment, it can also optionally comprise one or two overhangs and/orone or two caps. The RNAi agent is used to induce RNA interference ofthe target gene, KRAS.

Target and Complementary Sequences

The RNAi agents of the present disclosure target (e.g., specificallybind to, anneal to, etc.) the mRNA encoding the gene KRAS. The use ofthe RNAi agent specific to KRAS results in a decrease of KRAS activity,level and/or expression, e.g., a “knock-down” or “knock-out” of thetarget gene or target sequence. Particularly in one embodiment, in thecase of a disease state characterized by over-expression orhyper-activity of KRAS, administration of a RNAi agent to KRAS knocksdown the KRAS gene enough to restore a normal level of KRAS activity orexpression.

In one embodiment, the first or second strand of the RNAi comprises asequence complementary to that of the target nucleic acid, KRAS.

As used herein, the term “strand comprising a sequence” refers to anoligonucleotide comprising a chain of nucleotides that is described bythe sequence referred to using the standard nucleotide nomenclature.

As used herein, “target sequence” or “target gene” refer to a contiguousportion of the nucleotide sequence of an mRNA molecule formed during thetranscription of a gene, e.g., a KRAS gene, including mRNA that is aproduct of RNA processing of a primary transcription product. The targetportion of the sequence will be at least long enough to serve as asubstrate for iRNA-directed cleavage at or near that portion. Forexample, the target sequence will generally be from 9-36 nucleotides(“nt”) in length, e.g., 15-30 nt in length, including all sub-rangestherebetween. As non-limiting examples, the target sequence can be from15-30 nt, 15-26 nt, 15-23 nt, 15-22 nt, 15-21 nt, 15-20 nt, 15-19 nt,15-18 nt, 15-17 nt, 18-30 nt, 18-26 nt, 18-23 nt, 18-22 nt, 18-21 nt,18-20 nt, 19-30 nt, 19-26 nt, 19-23 nt, 19-22 nt, 19-21 nt, 19-20 nt, 19nt, 20-30 nt, 20-26 nt, 20-25 nt, 20-24 nt, 20-23 nt, 20-22 nt, 20-21nt, 20 nt, 21-30 nt, 21-26 nt, 21-25 nt, 21-24 nt, 21-23 nt, or 21-22nt, 21 nt, 22 nt, or 23 nt. The sense and antisense strands of the RNAicomprise a sequence complementary to that of the target nucleic acid,KRAS.

As used herein, and unless otherwise indicated, the term “complementary”refers to the ability of an oligonucleotide or polynucleotide comprisinga first nucleotide sequence to hybridize and form a duplex structureunder certain conditions with an oligonucleotide or polynucleotidecomprising a second nucleotide sequence. Such conditions can, forexample, be stringent, e.g., 400 mM NaCl, 40 mM PIPES pH 6.4, 1 mM EDTA,50° C. or 70° C. for 12-16 hours followed by washing. Other conditions,such as physiologically relevant conditions as may be encountered insidean organism, can apply. The skilled person will be able to determine theset of conditions most appropriate for a test of complementarity of twosequences in accordance with the ultimate application of the hybridizednucleotides.

Complementary sequences within a RNAi agent, e.g., within a dsRNA asdescribed herein, include base-paired oligonucleotides orpolynucleotides comprising a first nucleotide sequence to anoligonucleotide or polynucleotide comprising a second nucleotidesequence over the entire length of one or both nucleotide sequences.Such sequences can be referred to as “fully complementary” with respectto each other herein. However, where a first sequence is referred to as“substantially complementary” with respect to a second sequence herein,the two sequences can be fully complementary, or they may form one ormore, but generally not more than 5, 4, 3 or 2 mismatched base pairsupon hybridization for a duplex up to 30 base pairs, while retaining theability to hybridize under the conditions most relevant to theirultimate application, e.g., inhibition of gene expression via a RISCpathway. However, where two oligonucleotides are designed to form, uponhybridization, one or more single-stranded overhangs, such overhangsshall not be regarded as mismatches with regard to the determination ofcomplementarity. For example, a dsRNA comprising one oligonucleotide 21nucleotides in length and another oligonucleotide 23 nucleotides inlength, wherein the longer oligonucleotide comprises a sequence of 21nucleotides that is fully complementary to the shorter oligonucleotide,may yet be referred to as “fully complementary” for the purposesdescribed herein. The term “overhang” describes an unpaired nucleotideat the 3′ or 5′ end of a double-stranded nucleotide duplex, as describedabove. In one embodiment, the overhang is 1 to 4 nt long and is on the3′ end.

“Complementary” sequences, as used herein, may also include, or beformed entirely from, non-Watson-Crick base pairs and/or base pairsformed from non-natural and modified nucleotides, in as far as the aboverequirements with respect to their ability to hybridize are fulfilled.Such non-Watson-Crick base pairs includes, but are not limited to,Wobble or Hoogstein base pairing. The terms “complementary,” “fullycomplementary” and “substantially complementary” herein may furthermorebe used with respect to the base matching between the sense strand andthe antisense strand of a dsRNA, or between the antisense strand of aRNAi agent and a target sequence, as will be understood from the contextof their use. As used herein, a polynucleotide that is “substantiallycomplementary to at least part of” a messenger RNA (mRNA) refers to apolynucleotide that is substantially complementary to a contiguousportion of the mRNA of interest (e.g., an mRNA encoding KRAS). Forexample, a polynucleotide is complementary to at least a part of a KRASmRNA if the sequence is substantially complementary to a non-interruptedportion of an mRNA encoding KRAS.

Thus, the RNAi agent of the present disclosure is complimentary orsubstantially complimentary to a target sequence in the target KRAS andis double-stranded, comprising a sense and an antisense strand (whichcan be contiguous, linked via a loop, or otherwise joined), where thedouble-stranded region an be 9 to 36 bp long (particularly for example,19-22 bp or 19-23 bp long), and can furthermore optionally comprise a 3′or 5′ overhang, and the RNAi agent can furthermore comprise a 3′ cap.The RNAi agent mediates RNA interference, down-regulating or inhibitingthe level, expression and/or activity of KRAS, and/or establishing orre-establishing an approximately normal level of KRAS and/or KRASactivity, or other biological function related to KRAS.

Thus, the RNAi agent of the present disclosure is complimentary orsubstantially complimentary to a target sequence in the target KRAS andis double-stranded, comprising a sense and an antisense strand (whichcan be contiguous, linked via a loop, or otherwise joined), where thedouble-stranded region an be 9 to 36 bp long (particularly for example,19-22 bp or 19-23 bp long), and can furthermore optionally comprise a 3′or 5′ overhang, and the RNAi agent can furthermore comprise a 3′ cap.The RNAi agent mediates RNA interference, down-regulating or inhibitingthe level, expression and/or activity of KRAS, and/or establishing orre-establishing an approximately normal level of KRAS activity orexpression.

The term “double-stranded RNA” or “dsRNA,” as used herein, refers to anRNAi agent comprising a first and a second strand; e.g., a compositionthat includes an RNA molecule or complex of molecules having ahybridized duplex region that comprises two anti-parallel andsubstantially complementary nucleic acid strands, which will be referredto as having “sense” and “antisense” orientations with respect to atarget RNA. The antisense strand, with respect to the mRNA target, isalso called the “guide” strand, and the sense strand is also called the“passenger” strand. As used herein, depending on the context, the“first” strand can be the guide or antisense strand, and the “second”strand can be the passenger or sense strand. Also as used herein, againdepending on the context, the “first” strand can be the passenger orsense strand, and the “second” strand can be the guide or antisense. Thepassenger strand can include at least one or more of the following: oneor more extra nucleotides (e.g., a bulge or 1 nt loop) compared to theother strand, a nick, a gap, etc., compared to the other strand. Invarious embodiments, the first strand is the sense strand and the secondstrand is the anti-sense strand. In other embodiments, the first strandis the anti-sense strand, and the second strand is the sense strand.

The duplex region can be of any length that permits loading into theRISC complex and subsequent specific degradation of a desired target RNAthrough a RISC pathway, but will typically range from 9 to 36 base pairs(“bp”) in length, e.g., 15-30 base pairs in length. Considering a duplexbetween 9 and 36 base pairs, the duplex can be any length in this range,for example, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 bp and anysub-range therebetween, including, but not limited to 15-30 base pairs,15-26 bp, 15-23 bp, 15-22 bp, 15-21 bp, 15-20 bp, 15-19 bp, 15-18 bp,15-17 bp, 18-30 bp, 18-26 bp, 18-23 bp, 18-22 bp, 18-21 bp, 18-20 bp,19-30 bp, 19-26 bp, 19-23 bp, 19-22 bp, 19-21 bp, 19-20 bp, 19 bp, 20-30bp, 20-26 bp, 20-25 bp, 20-24 bp, 20-23 bp, 20-22 bp, 20-21 bp, 20 bp,21-30 bp, 21-26 bp, 21-25 bp, 21-24 bp, 21-23 bp, 21-22 bp, 21 bp, 22bp, or 23 bp.

The dsRNAs generated in the cell by processing with Dicer and similarenzymes are generally in the range of about 19 to about 22 base pairs inlength, although artificial RNAi agents can be synethesized or made byany method known in the art. One strand of the duplex region of a dsRNAcomprises a sequence that is substantially complementary to a region ofa target RNA. The two strands forming the duplex structure can be from asingle RNA molecule having at least one self-complementary duplexregion, or can be formed from two or more separate RNA molecules thathybridize to form the duplex. Where the duplex region is formed from twoself-complementary regions of a single molecule, the molecule can have aduplex region separated by a single stranded chain of nucleotides(herein referred to as a “hairpin loop”, e.g., such as found in an shRNAconstruct) between the 3′-end of one strand and the 5′-end of therespective other strand forming the duplex structure. The hairpin loopcan comprise at least one unpaired nucleotide; in some embodiments thehairpin loop can comprise at least 3, at least 4, at least 5, at least6, at least 7, at least 8, at least 9, at least 10, at least 20, atleast 23 or more unpaired nucleotides. Where the two substantiallycomplementary strands of a dsRNA are comprised by separate RNAmolecules, those molecules need not, but can be covalently connected.Where the two strands are connected covalently by a hairpin loop, theconstruct is generally referred to herein and in the art as a “shRNA”.Where the two strands are connected covalently by means other than ahairpin loop, the connecting structure is referred to as a “linker.” Theterm “siRNA” is also used herein to refer to a dsRNA as described above.

RNAi Agents Lowering or Normalizing KRAS Level, Expression and/orActivity

RNAi agents for targeting KRAS include those which bind to a KRASsequence provided herein and which work to reduce KRAS through a RNAimechanism. Example RNAi agents (e.g., siRNAs) to KRAS are provided,e.g., in Table 1.

Any method known in the art can be use to measure changes in KRASactivity, level, and/or expression induced by a KRAS RNAi agent.Measurements can be performed at multiple timepoints, prior to, duringand after administration of the RNAi agent, to determine the effect ofthe RNAi agent.

The RNAi agents of the present disclosure silence, inhibit theexpression of, down-regulate the expression of, and/or suppress theexpression of KRAS, such that an approximately normal level of KRASactivity or expression is restored.

In addition, in various embodiments, depending on the disease conditionand biological context, it is acceptable to use the RNAi agents of thepresent disclosure to establish a level of KRAS expression, activityand/or level which is below the normal level, or above the normal level,depending on the therapeutic outcome that is desired.

Any method known in the art can be use to measure changes in KRASactivity, level and/or expression induced by a KRAS siRNA. Measurementscan be performed at multiple timepoints, prior to, during and afteradministration of the siRNA, to determine the effect of the siRNA.

The terms “silence,” “inhibit the expression of,” “down-regulate theexpression of,” “suppress the expression of,” and the like, in so far asthey refer to a KRAS gene, herein refer to the at least partialsuppression of the expression of a KRAS gene, as manifested by areduction of the amount of KRAS mRNA which may be isolated from ordetected in a first cell or group of cells in which a KRAS gene istranscribed and which has or have been treated such that the expressionof a KRAS gene is inhibited, as compared to a second cell or group ofcells substantially identical to the first cell or group of cells butwhich has or have not been so treated (control cells). The degree ofinhibition is usually expressed in terms of

$\begin{matrix}{{\frac{\begin{matrix}{( {{mRNA}\mspace{14mu} {in}\mspace{14mu} {control}\mspace{14mu} {cells}} ) -} \\( {{mRNA}\mspace{14mu} {in}\mspace{14mu} {treated}\mspace{14mu} {cells}} )\end{matrix}}{( {{mRNA}\mspace{14mu} {in}\mspace{14mu} {control}\mspace{14mu} {cells}} )} \cdot 100}\%} & {{Equation}\mspace{14mu} 1}\end{matrix}$

Alternatively, the degree of inhibition may be given in terms of areduction of a parameter that is functionally linked to KRAS geneexpression, e.g., the amount of protein encoded by a KRAS gene,alteration in expression of a protein whose expression is dependent onKRAS, etc. In principle, KRAS gene silencing may be determined in anycell expressing KRAS, either constitutively or by genomic engineering,and by any appropriate assay. However, when a reference or control isneeded in order to determine whether a given RNAi agent inhibits theexpression of KRAS by a certain degree and therefore is encompassed bythe instant disclosure, the assays provided in the Examples below shallserve as such reference.

For example, in certain instances, expression of KRAS is suppressed byat least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% byadministration of a RNAi agent featured in the present disclosure. Insome embodiments, KRAS is suppressed by at least about 60%, 70%, or 80%by administration of a RNAi agent featured in the present disclosure. Insome embodiments, KRAS is suppressed by at least about 85%, 90%, or 95%or more by administration of a RNAi agent, as described herein. In oneembodiment, the degree of KRAS suppression is determined by loss of fulllength KRAS mRNA in a treated cell compared to an untreated cell. In oneembodiment, the degree of KRAS suppression is determined with aphenotypic assay that monitors loss of proliferative activity and/orcell death. Other embodiments are as provided in the Examples.

The ability of a RNAi agent to suppress KRAS can be first tested invitro (e.g., using test cells such as RKO).

RNAi agents which can suppress KRAS in vitro can then be tested forimmunostimulation using, for example, a PBMC (peripheral bloodmononuclear cell) assay. RNAi agents can also be tested in animal tests.Test and control animals include those which over-express orunder-express KRAS, as described in, for example, Hummer et al. 2005 J.Am. Soc. Nephrol. 16: 3160-3166; Randrianarison et al. 2007 Am. J.Physiol. Lung Cell. Mol. Physiol. 294: 409-416; Cao et al. 2006 Am. J.Physiol. Renal Physiol., and references cited therein. RNAi agents whichsuppress or alter the level, activity and/or expression of KRAS can beused in medicaments to treat various KRAS-related diseases.

By “lower” in the context of KRAS or a symptom of a KRAS-related diseaseis meant a statistically significant decrease in such level. Thedecrease can be, for example, at least 10%, at least 20%, at least 30%,at least 40% or more. If, for a particular disease, or for an individualsuffering from a particular disease, the levels or expression of KRASare elevated, treatment with a KRAS RNAi agent of the present disclosurecan particularly reduce the level or expression of KRAS to a levelconsidered in the literature as within the range of normal for anindividual without such disorder, or to a level that reduces orameliorates symptoms of a disease. The level or expression of KRAS canbe measured by evaluation of mRNA (e.g., via Northern blots or PCR), orprotein (e.g., Western blots). The effect of a RNAi agent on KRASexpression can be determined by measuring KRAS gene transcription rates(e.g., via Northern blots; or reverse transcriptase polymerase chainreaction or real-time polymerase chain reaction).

As used herein, “down-regulates” refers to any statistically significantdecrease in a biological activity and/or expression of KRAS, includingfull blocking of the activity (i.e., complete inhibition) and/orexpression. For example, “down-regulation” can refer to a decrease of atleast about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% in KRAS level,activity and/or expression.

As used herein, the term “inhibit” or “inhibiting” KRAS refers to anystatistically significant decrease in biological level, activity and/orexpression of KRAS, including full blocking of the activity and/orexpression. For example, “inhibition” can refer to a decrease of atleast about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% in KRAS level,activity and/or expression. As used herein, the term “inhibit” similarlyrefers to a significant decrease in level, activity and/or expression,while referring to any other biological agent or composition.

By “level”, it is meant that the KRAS RNAi agent can alter the level ofKRAS, e.g., the level of KRAS mRNA or the level of KRAS protein, or thelevel of activity of KRAS.

Some diseases, such as types of a proliferative disease, includingwithout limitation a solid or liquid cancer, adenocarcinoma, colorectalcancer, advanced and/or metastatic colorectal cancer, colon cancer,lung, non-small cell lung cancer and lung adenocarcinoma, acutemyelogenous lung, bladder, brain, breast, cervical, endometrial,gastric, head and neck, kidney, leukemia, myelodysplastic syndrome,myeloid leukemia, liver, melanoma, ovarian, pancreatic, prostate,testicular, thyroid cancers, and cardio-facio-cutaneous (CFC) syndromeand Noonan syndrome, and similar and related diseases, are characterizedby a KRAS mutation or excessive KRAS abundance or activity. Particularlyin one embodiment, in the case of a disease characterized byover-expression and/or hyper-activity of KRAS, administration of a RNAiagent to KRAS reduces the level, expression and/or activity of KRAS.Thus, in various embodiments, administration of a RNAi agent to KRASparticularly establishes or re-establishes a normal or approximatelynormal level of KRAS activity, expression and/or level.

By “normal” or “approximately normal” in terms of level, expressionand/or activity, is meant at least: about 50%, about 60%, about 70%,about 80%, about 90%, and/or about 100%; and/or no more than: about100%, about 120%, about 130%, about 140%, or about 150% of the level,expression or activity of KRAS in a healthy cell, tissue, or organ. Thiscan be measured using, for example, lung or kidney homogenates, asdescribed in Gambling et al. 2004 Kidney Intl. 65: 1774-1781.Particularly in one embodiment, administration of the appropriate amountof the appropriate KRAS RNAi agent restores KRAS level, activity and/orexpression to about 50% to about 150%, more particularly about 60% toabout 140%, more particularly to about 70% to about 130%, moreparticularly to about 80% to about 120%, more particularly to about 90%to about 110%, and most particularly to about 100% of that of a healthycell, tissue or organ. Administration of a KRAS RNAi to a patient with aKRAS-related disease thus particularly restores the level, activity,and/or expression of KRAS and the level of Na⁺ reabsorption to anapproximately normal level, as determined by direct measurements of KRASmRNA or protein levels, or indirect determinations. In addition, thepreferred target amount of KRAS level, expression and/or activity afterKRAS RNAi agent administration can be calculated to take into accountany other perturbations in a KRAS-related pathway. For example, ifanother factor in a KRAS-related pathway is either over- orunder-expressed, KRAS level, expression or activity may be modulated toattain a more normal state.

In addition, in various embodiments, depending on the disease conditionand biological context, it is acceptable to use the RNAi agents of thepresent disclosure to establish a level of KRAS expression, activityand/or level which is below the normal level, or above the normal level.

Types of RNAi Agents and Modification Thereof

The use of RNAi agents or compositions comprising an antisense nucleicacid to down-modulate the expression of a particular protein in a cellis well known in the art. A RNAi agent comprises a sequencecomplementary to, and is capable of hydrogen bonding to, the codingstrand of another nucleic acid (e.g., an mRNA). Thus, in variousembodiments, the RNAi agents of the present disclosure encompass anyRNAi agents which target (e.g., are complementary, capable ofhybridizing or hydrogen bonding to, etc.) any sequence presented, e.g.,in any of Tables 1 to 6.

Once a functional guide strand has been identified, many variations tothe guide and/or passenger strand can be made. For example, the RNAiagent may have modifications internally, or at one or both ends. Themodifications at the ends can help stabilize the RNAi agent, protectingit from degradation by nucleases in the blood. The RNAi agents mayoptionally be directed to regions of the KRAS mRNA known or predicted tobe near or at splice sites of the gene.

A RNAi agent can be constructed using chemical synthesis and enzymaticligation reactions using procedures known in the art. For example, RNAiagent can be chemically synthesized using naturally-occurringnucleotides or variously modified nucleotides designed to decreaseoff-target effects, and/or increase the biological stability of themolecules or to increase the physical stability of the duplex formedbetween the antisense and sense nucleic acids, e.g., phosphorothioatederivatives and acridine substituted nucleotides can be used.

“G,” “C,” “A,” “T” and “U” each generally stand for a nucleotide thatcontains guanine, cytosine, adenine, thymidine and uracil as a base,respectively. However, the terms “ribonucleotide”, “deoxynucleotide”, or“nucleotide” can also refer to a modified nucleotide or a surrogatereplacement moiety. The skilled person is well aware that guanine,cytosine, adenine, and uracil may be replaced by other moieties withoutsubstantially altering the base pairing properties of an oligonucleotidecomprising a nucleotide bearing such replacement moiety. For example,without limitation, a nucleotide comprising inosine as its base may basepair with nucleotides containing adenine, cytosine, or uracil. Hence,nucleotides containing uracil, guanine, or adenine may be replaced inthe nucleotide sequences of dsRNA featured in the present disclosure bya nucleotide containing, for example, inosine. In another example,adenine and cytosine anywhere in the oligonucleotide can be replacedwith guanine and uracil, respectively to form Wobble base pairing withthe target mRNA. Sequences containing such replacement moieties aresuitable for the compositions and methods featured in the presentdisclosure.

The skilled artisan will recognize that the term “RNA molecule” or“ribonucleic acid molecule” encompasses not only RNA molecules asexpressed or found in nature (i.e., are naturally occurring), but alsonon-naturally occurring analogs and derivatives of RNA comprising one ormore ribonucleotide/ribonucleoside analogs or derivatives as describedherein or as known in the art. The RNA can be modified in the nucleobasestructure or in the ribose-phosphate backbone structure, e.g., asdescribed herein below. However, the molecules comprising ribonucleosideanalogs or derivatives must retain the ability to form a duplex. Asnon-limiting examples, an RNA molecule can also include at least onemodified ribonucleoside, including but not limited to a 2′-O-methylmodified nucleotide, a nucleoside comprising a 5′ phosphorothioategroup, a terminal nucleoside linked to a cholesteryl derivative ordodecanoic acid bisdecylamide group, a locked nucleoside, an abasicnucleoside, a 2′-deoxy-2′-fluoro modified nucleoside, a2′-amino-modified nucleoside, 2′-alkyl-modified nucleoside, morpholinonucleoside, an unlocked ribonucleotide (e.g., an acyclic nucleotidemonomer, as described in WO 2008/147824), a phosphoramidate or anon-natural base comprising nucleoside, or any combination thereof.Alternatively, an RNA molecule can comprise at least two modifiedribonucleosides, at least 3, at least 4, at least 5, at least 6, atleast 7, at least 8, at least 9, at least 10, at least 15, at least 20or more, up to the entire length of the dsRNA molecule. Themodifications need not be the same for each of such a plurality ofmodified ribonucleosides in an RNA molecule. In one embodiment, modifiedRNAs contemplated for use in methods and compositions described hereinare peptide nucleic acids (PNAs) that have the ability to form therequired duplex structure and that permit or mediate the specificdegradation of a target RNA via a RISC pathway.

Examples of modified nucleotides which can be used to generate the RNAiagent include 5-fluorouracil, 5-bromouracil, 5-chlorouracil,5-iodouracil, hypoxanthine, xantine, 4-acetylcytosine,5-(carboxyhydroxylmethyl) uracil,5-carboxymethylaminomethyl-2-thiouridine,5-carboxymethylaminomethyluracil, dihydrouracil,beta-D-galactosylqueosine, inosine, N6-isopentenyladenine,1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine,2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine,7-methylguanine, 5-methylaminomethyluracil,5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine,5′-methoxycarboxymethyluracil, 5-methoxyuracil,2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v),wybutoxosine, pseudouracil, queosine, 2-thiocytosine,5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil,uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v),5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w,and 2,6-diaminopurine.

A “modified variant” of a sequence disclosed herein includes any variantcomprising the same sequence, but with a modification in the base,sugar, phosphate or backbone (but not a base substitution, e.g., A forG, or C for U). Thus, a modified variant can comprise any modifiednucleotide described above (e.g., 5-fluorouracil, 5-bromouracil,5-chlorouracil, 5-iodouracil, hypoxanthine, xantine, 4-acetylcytosine,5-(carboxyhydroxylmethyl) uracil, etc.). When a base is replaced by acorresponding modified base (e.g., A for modified A), these modifiednucleotides do not constitute a mismatch or base difference. Thus agiven sequence with a U at a particular position and a modified variantcomprising a 5-fluorouracil, 5-bromouracil, 5-chlorouracil, or5-iodouracil at the same sequence would differ by 0 nt (or have nomismatches); however, a given sequence with a C at a particular positionand a different sequence with a 5-fluorouracil (wherein the twosequences are otherwise identical) would differ by 1 nt (1 mismatch).

Replacing the 3′-terminal nucleotide overhanging segments of a 21-mersiRNA duplex having two-nucleotide 3′-overhangs withdeoxyribonucleotides does not have an adverse effect on RNAi activity.Replacing up to four nucleotides on each end of the siRNA withdeoxyribonucleotides has been well tolerated, whereas completesubstitution with deoxyribonucleotides results in no RNAi activity.International PCT Publication No. WO 00/44914, and Beach et al.International PCT Publication No. WO 01/68836 preliminarily suggest thatsiRNA may include modifications to either the phosphate-sugar backboneor the nucleoside to include at least one of a nitrogen or sulfurheteroatom. Kreutzer et al. Canadian Patent Application No. 2,359,180,also describe certain chemical modifications for use in dsRNA constructsin order to counteract activation of double-stranded RNA-dependentprotein kinase PKR, specifically 2′-amino or 2′-O-methyl nucleotides,and nucleotides containing a 2′-0 or 4′-C methylene bridge. Additional3′-terminal nucleotide overhangs include dT (deoxythimidine),2′-0,4′-C-ethylene thymidine (eT), and 2-hydroxyethyl phosphate (hp).4-thiouracil and 5-bromouracil substitutions can also be made. Parrishet al. 2000 Molecular Cell 6: 1077-1087.

Those skilled in the art will appreciate that it is possible tosynthesize and modify the siRNA as desired, using any conventionalmethod known in the art (see Henschel et al. 2004 DEQOR: a web-basedtool for the design and quality control of siRNAs. Nucleic AcidsResearch 32 (Web Server Issue): W113-W120). In addition, if the RNAiagent is a shRNA, it will be apparent to those skilled in the art thatthere are a variety of regulatory sequences (for example, constitutiveor inducible promoters, tissue-specific promoters or functionalfragments thereof, etc.) which are useful for shRNA expressionconstruct/vector.

There are several examples in the art describing sugar, base, phosphateand backbone modifications that can be introduced into nucleic acidmolecules with significant enhancement in their nuclease stability andefficacy. For example, oligonucleotides are modified to enhancestability and/or enhance biological activity by modification withnuclease resistant groups, for example, 2′-amino, 2′-C-allyl, 2′-flouro,2′-O-methyl, 2′-O-allyl, 2′-H, nucleotide base modifications (for areview see Usman and Cedergren 1992 TIBS. 17: 34; Usman et al. 1994Nucleic Acids Symp. Ser. 31: 163; Burgin et al. 1996 Biochemistry 35:14090). Sugar modification of nucleic acid molecules are extensivelydescribed in the art.

In various embodiments, the RNAi agent comprises a 2′-modificationselected from the group consisting of: 2′-deoxy, 2′-deoxy-2′-fluoro,2′-O-methyl, 2′-O-methoxyethyl (2′-O-MOE), 2′-O-aminopropyl (2′-O-AP),2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-O-dimethylaminopropyl(2′-O-DMAP), 2′-O-dimethylaminoethyloxyethyl (2′-O-DMAEOE), and2′-O-N-methylacetamido (2′-O-NMA).

Additional modifications and conjugations of RNAi agents have beendescribed. Soutschek et al. 2004 Nature 432: 173-178 presentedconjugation of cholesterol to the 3′-end of the sense strand of a siRNAmolecule by means of a pyrrolidine linker, thereby generating a covalentand irreversible conjugate. Chemical modifications (includingconjugation with other molecules) of RNAi agents may also be made toimprove the in vivo pharmacokinetic retention time and efficiency.

In various embodiments, the RNAi agent to KRAS comprises at least one5′-uridine-adenine-3′ (5′-ua-3′) dinucleotide, wherein the uridine is a2′-modified nucleotide; at least one 5′-uridine-guanine-3′ (5′-ug-3′)dinucleotide, wherein the 5′-uridine is a 2′-modified nucleotide; atleast one 5′-cytidine-adenine-3′ (5′-ca-3′) dinucleotide, wherein the5′-cytidine is a 2′-modified nucleotide; and/or at least one5′-uridine-uridine-3′ (5′-uu-3′) dinucleotide, wherein the 5′-uridine isa 2′-modified nucleotide. In certain embodiments, the RNAi agent cancomprise a non-natural nucleobase, wherein the non-natural nucleobase isdifluorotolyl, nitroindolyl, nitropyrrolyl, or nitroimidazolyl. In aparticular embodiment, the non-natural nucleobase is difluorotolyl. Incertain embodiments, only one of the two oligonucleotide strandscontains a non-natural nucleobase. In certain embodiments, both of theoligonucleotide strands contain a non-natural nucleobase.

In another embodiment, the RNAi comprises a gap or contains mismatchcomprising an abasic nucleotide.

In another embodiment, the RNAi agent has a single-stranded nick (e.g.,a break or missing bond in the backbone). In various embodiments, asingle-stranded nick can be in either the sense or anti-sense strand, orboth.

This nick can be, for example, in the sense strand, producing a smallinternally segmented interfering RNA, or sisiRNA, which may have lessoff-target effects than the corresponding RNAi agent without a nick.See, for example, WO 2007/107162 to Wengels and Kjems.

The antisense nucleic acid or RNAi agent can also have an alternativebackbone such as locked nucleic acids (LNA), Morpholinos, peptidicnucleic acids (PNA), threose nucleic acid (TNA), or glycol nucleic acid(GNA), or FANA and/or it can be labeled (e.g., radiolabeled or otherwisetagged). FANA are described in Dowler et al. 2006 Nucl. Acids Res. 34:1669-1675.

One or both strands can comprise an alternative backbone.

In yet another embodiment, the RNAi agent employed by the methods of thepresent disclosure can include an α-anomeric nucleic acid molecule. Anα-anomeric nucleic acid molecule forms specific double-stranded hybridswith complementary RNA in which, contrary to the usual β-units, thestrands run parallel to each other. Gaultier et al. 1987 Nucleic Acids.Res. 15: 6625-6641.

The antisense nucleic acid molecule can also comprise a2′-o-methylribonucleotide (Inoue et al. 1987 Nucleic Acids Res. 15:6131-6148) or a chimeric RNA-DNA analogue (Inoue et al. 1987 FEBS Lett.215: 327-330).

Other modifications and/or other changes can be made to the RNAi agent.A portion of the RNAi agent can be double-stranded DNA, while anotherportion is double-stranded RNA, forming a DNA-RNA chimera (See, forexample, Yamato et al. 2011. Cancer Gene Ther. 18: 587-597). Mismatchesbetween the guide and passenger stand can also be introduced, thoughsome positions may be better suited than others (See, for example, U.S.Patent App. No. 2009/0209626 to Khvorova). The passenger strand can alsobe shortened, to as short as 15 or 16 nt, while the guide strand remains19 nt or longer (See, for example, Sun et al. 2008 Nature Biotech. 26:1379-1382; and Chu and Rana 2008 RNA 14: 1714-1719). This can increaseincorporation of the guide strand into the RNA-induced Silence Complex(RISC), and decrease incorporation of the passenger strand, thanreducing off-target effects. In some cases, the passenger strand may bemore amenable to modification (e.g., single-stranded nicking, nucleotidemodifications, and shortening) than the guide strand.

These and many other modifications can be made once a functional guidestrand is identified.

Pharmaceutical Compositions of RNAi Agents

As used here, a “pharmaceutical composition” comprises apharmaceutically effective amount of one or more KRAS RNAi agent, apharmaceutically acceptable carrier, and, optionally, an additionaldisease treatment which works synergistically with the RNAi agent. Asused herein, “pharmacologically effective amount,” “therapeuticallyeffective amount” or simply “effective amount” refers to that amount ofa RNAi agent effective to produce the intended pharmacological,therapeutic or preventive result. For example, if a given clinicaltreatment is considered effective where there is at least a 10%reduction in a measurable parameter associated with a disease ordisorder, a therapeutically effective amount of a drug for the treatmentof that disease or disorder is the amount necessary to effect at least a10% reduction in that parameter. In this embodiment, a therapeuticallyeffective amount of a RNAi agent targeting KRAS can reduce KRAS proteinlevels by at least 10%. In additional embodiments, a given clinicaltreatment is considered effective where there is at least a 15, 20, 25,30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95% reduction in ameasurable parameter associated with a disease or disorder, and thetherapeutically effective amount of a drug for the treatment of thatdisease or disorder is the amount necessary to effect at least a 15, 20,25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95% reduction,respectively, in that parameter.

The term “pharmaceutically acceptable carrier” refers to a carrier foradministration of a therapeutic agent. Such carriers include, but arenot limited to, lipid nanoparticles, saline, buffered saline, dextrose,water, glycerol, ethanol, and combinations thereof. The termspecifically excludes cell culture medium. Any appropriate phamaceuticalcarrier known in the art can be used in conjunction with the RNAi agentsdisclosed herein.

Pharmaceutical Composition Comprising a RNAi Agent to KRAS

Additional components of a pharmaceutical composition comprising a RNAiAgent to KRAS are contemplated to aid in delivery, stability, efficacy,or reduction of immunogenicity.

Liposomes have been used previously for drug delivery (e.g., delivery ofa chemotherapeutic). Liposomes (e.g., cationic liposomes) are describedin PCT publications W002/100435A1, W003/015757A1, W004029213A2; andWO/2011/076807; U.S. Pat. Nos. 5,962,016; 5,030,453; and 6,680,068; andU.S. Patent Application 2004/0208921. A process of making liposomes isalso described in W004/002453A1. Furthermore, neutral lipids have beenincorporated into cationic liposomes (e.g., Farhood et al. 1995), aswell as PEGylated lipids.

Cationic liposomes have been used to deliver RNAi agent to various celltypes (Sioud and Sorensen 2003; U.S. Patent Application 2004/0204377;Duxbury et al., 2004; Donze and Picard, 2002).

Use of neutral liposomes disclosed in Miller et al. 1998, and U.S.Patent Application 2003/0012812.

As used herein, the term “SNALP” refers to a stable nucleic acid-lipidparticle. A SNALP represents a vesicle of lipids coating a reducedaqueous interior comprising a nucleic acid such as an iRNA or a plasmidfrom which an iRNA is transcribed. SNALPs are described, e.g., in U.S.Patent Application Publication Nos. 20060240093, 20070135372, and inInternational Application No. WO 2009082817.

Chemical transfection using lipid-based, amine-based and polymer-basedtechniques, is disclosed in products from Ambion Inc., Austin, Tex.; andNovagen, EMD Biosciences, Inc, an Affiliate of Merck KGaA, Darmstadt,Germany); Ovcharenko D (2003) “Efficient delivery of siRNAs to humanprimary cells.” Ambion TechNotes 10 (5): 15-16). Additionally, Song etal. (Nat Med. published online (Feb. 10, 2003) doi: 10.1038/nm828) andothers [Caplen et al. 2001 Proc. Natl. Acad. Sci. (USA), 98: 9742-9747;and McCaffrey et al. Nature 414: 34-39] disclose that liver cells can beefficiently transfected by injection of the siRNA into a mammal'scirculatory system.

A variety of molecules have been used for cell-specific RNAi agentdelivery. See, for example, WO/2011/076807. For example, the nucleicacid-condensing property of protamine has been combined with specificantibodies to deliver siRNAs. Song et al. 2005 Nat Biotech. 23: 709-717.The self-assembly PEGylated polycation polyethylenimine (PEI) has alsobeen used to condense and protect siRNAs. Schiffelers et al. 2004 Nucl.Acids Res. 32: e149, 141-110.

The RNAi agents of the present disclosure can be delivered via, forexample, Lipid nanoparticles (LNP); neutral liposomes (NL); polymernanoparticles; double-stranded RNA binding motifs (dsRBMs); or viamodification of the RNAi agent (e.g., covalent attachment to the dsRNA)or by any method known in the art for delivery of a RNAi agentcomprising nucleic acids.

Lipid nanoparticles (LNP) are self-assembling cationic lipid basedsystems. These can comprise, for example, a neutral lipid (the liposomebase); a cationic lipid (for siRNA loading); cholesterol (forstabilizing the liposomes); and PEG-lipid (for stabilizing theformulation, charge shielding and extended circulation in thebloodstream).

The cationic lipid can comprise, for example, a headgroup, a linker, atail and a cholesterol tail. The LNP can have, for example, good tumordelivery, extended circulation in the blood, small particles (e.g., lessthan 100 nm), and stability in the tumor microenvironment (which has lowpH and is hypoxic).

Neutral Liposomes (NL) are Non-Cationic Lipid Based Particles.

Polymer nanoparticles are self-assembling polymer-based particles.

Double-stranded RNA binding motifs (dsRBMs) are self-assembling RNAbinding proteins, which will need modifications.

In various embodiments, the RNAi agent to KRAS is packaged as amonotherapy into a delivery vehicle, or may be further ligated to one ormore diagnostic compound, reporter group, cross-linking agent,nuclease-resistance conferring moiety, natural or unusual nucleobase,lipophilic molecule, cholesterol, lipid, lectin, steroid, uvaol,hecigenin, diosgenin, terpene, triterpene, sarsasapogenin, Friedelin,epifriedelanol-derivatized lithocholic acid, vitamin, carbohydrate,dextran, pullulan, chitin, chitosan, synthetic carbohydrate, oligolactate 15-mer, natural polymer, low- or medium-molecular weightpolymer, inulin, cyclodextrin, hyaluronic acid, protein, protein-bindingagent, integrin-targeting molecule, polycationic, peptide, polyamine,peptide mimic, and/or transferrin.

The RNAi agents of the present disclosure can be prepared in apharmaceutical composition comprising various components appropriate forthe particular method of administration of the RNAi agent.

KRAS-Related Diseases

The present disclosure encompasses RNAi agents to KRAS andadministration of the RNAi agents to humans and non-human animals totreat various KRAS-related diseases.

By “KRAS-related disease” is meant any disease related to a dysfunctionin the level, expression and/or activity of KRAS, and/or any diseasewhich can be treated and/or ameliorated by modulating the level,expression and/or activity of KRAS. In particular, it includes aproliferative disease, including without limitation a solid or liquidcancer, e.g., adenocarcinoma, colorectal cancer, advanced and/ormetastatic colorectal cancer, colon cancer, lung, non-small cell lungcancer and lung adenocarcinoma, acute myelogenous lung, bladder, brain,breast, cervical, endometrial, gastric, head and neck, kidney, leukemia,myelodysplastic syndrome, myeloid leukemia, liver, melanoma, ovarian,pancreatic, prostate, testicular, thyroid cancers, andcardio-facio-cutaneous (CFC) syndrome and Noonan syndrome, and similarand related diseases.

For additional information on KRAS-related diseases, see, for example:Bos. 1989. Cancer Res. 49. 17: 4682-9; Engelman et al. 2008. Nature Med.14: 1351-1356; Haigis et al. 2008 Nature Gen. 40: 600-608; Karapetis etal. 2008 N. E. J. Med. 359: 1757-1765; Kiaris et al. 1995. Int. J.Oncol. 7: 413-421; Liu et al. 1987 Nature 330: 186-188; Riely et al.2008 Clin. Cancer Res. 14: 5731; and Riely et al. 2009. Proc. Am.Thorac. Soc. 6: 201-205. KRAS mutation, hyperactivity or over-expressionis also associated with cardio-facio-cutaneous (CFC) syndrome and Noonansyndrome. Adachi et al. 2012 Seizure: Eur. J. Epilepsy 21: 55-60; Kim etal. 2011. J. Korean Soc. Neonatol. 18: 374-378.

RNAi agents to KRAS can thus be used to treat KRAS-related diseases,particularly those diseases associated with altered expression, activityand/or levels of KRAS.

Use of RNAi Agents for Treatment of KRAS-Related Diseases

The RNAi agents to KRAS described herein can be formulated intopharmaceutical compositions which can be administered to humans ornon-human animals. These compositions can comprise one or more RNAiagents, and, optionally, additional treatments useful for treatingKRAS-related diseases. They can be administered as part of anearly/preventative treatment, and can be administered in atherapeutically-effective dosage. The pharmaceutical composition cancomprise a pharmaceutical carrier and can be administered by any methodknown in the art. These various aspects of the present disclosure aredescribed in additional detail below.

RNAi agents to KRAS can be administered to humans and non-human animalsfor treatment of KRAS-related diseases.

In one embodiment of the present disclosure, the compositions comprisinga KRAS RNAi agent can be administered to non-human animals. For example,the compositions can be given to chickens, turkeys, livestock animals(such as sheep, pigs, horses, cattle, etc.), companion animals (e.g.,cats and dogs) and can have efficacy in treatment of proliferativedisease, cardio-facio-cutaneous (CFC) syndrome or Noonan syndrome, andsimilar diseases. In each case, the RNAi agent to KRAS would be selectedto match the sequence of the KRAS of the genome of the animal, and to,particularly, contain at least 1 nt mismatch from all other genes inthat animal's genome. The RNAi agents of the present disclosure can thusbe used in treatment of KRAS-related diseases in humans and non-humananimals.

As used herein in the context of KRAS expression, the terms “treat,”“treatment,” and the like, refer to relief from or alleviation ofpathological processes mediated by KRAS expression. In the context ofthe present disclosure insofar as it relates to any of the otherconditions recited herein below (other than pathological processesmediated by KRAS expression), the terms “treat,” “treatment,” and thelike mean to relieve or alleviate at least one symptom associated withsuch condition, or to slow or reverse the progression or anticipatedprogression of such condition, such as slowing the progression of alipid disorder, such as atherosclerosis.

By “treatment” is also meant prophylaxis, therapy, cure, or any otherchange in a patient's condition indicating improvement or absence ofdegradation of physical condition. By “treatment” is meant treatment ofKRAS-related disease (e.g., a proliferative disease, including withoutlimitation a solid or liquid cancer, adenocarcinoma, colorectal cancer,advanced and/or metastatic colorectal cancer, colon cancer, lung,non-small cell lung cancer and lung adenocarcinoma, acute myelogenouslung, bladder, brain, breast, cervical, endometrial, gastric, head andneck, kidney, leukemia, myelodysplastic syndrome, myeloid leukemia,liver, melanoma, ovarian, pancreatic, prostate, testicular, thyroidcancers, or cardio-facio-cutaneous (CFC) syndrome or Noonan syndrome),or any appropriate treatment of any other ailment the patient has. Asused herein, the terms “treatment” and “treat” refer to bothprophylactic and preventative treatment and curative ordisease-modifying treatment, including treatment of patients at risk ofcontracting a disease or suspected of having a disease, as well aspatients already ill or diagnosed as suffering from a condition. Theterms “treatment” and “treat” also refer to the maintenance and/orpromotion of health in an individual not suffering from a disease butwho may be susceptible to developing an unhealthy condition, such asnitrogen imbalance or muscle loss. In one embodiment, “treatment” doesnot encompass prevention of a disease state. Thus, the presentdisclosure is useful for suppressing expression of KRAS and/or treatinga KRAS-related disease in an individual afflicted by a KRAS-relateddisease, or an individual susceptible to a KRAS-related disease. Anindividual “afflicted” by a KRAS-related disease has demonstrateddetectable symptoms characteristics of the disease, or had otherwisebeen shown clinically to have been exposed to or to carry KRAS-relateddisease pathogens or markers. As non-limiting examples, an individualafflicted by a KRAS-related disease can show outward symptoms; or canshow no outward symptoms but can be shown with a clinical test to carryprotein markers associated with a KRAS-related disease, or proteins orgenetic material associated with a pathogen in the blood.

Early treatment of some KRAS-related diseases may be more efficacious ifadministered early rather than later. Thus, in one particularembodiment, the RNAi agent to KRAS is administered early, prior todisease manifestation, and/or as a preventative agent, rather thanadministered after disease establishment.

Treatments of KRAS-related diseases can comprise various treatments,comprising a KRAS RNAi agent, and optionally further comprising anadditional treatment, which can be a method (or procedure), or anadditional composition (e.g., an agent or additional RNAi agent).

Dosages and Effective Amounts of RNAi Agents

The RNAi agents of the present disclosure are administered in a dosageof a therapeutically effective amount to a patient in need thereof.

An “effective amount” or a “therapeutically effective amount” is anamount that treats a disease or medical condition of an individual, or,more generally, provides a nutritional, physiological or medical benefitto an individual. As used herein, the phrases “therapeutically effectiveamount” and “prophylactically effective amount” refer to an amount thatprovides a therapeutic benefit in the treatment, prevention, ormanagement of pathological processes mediated by KRAS expression or anovert symptom of pathological processes mediated by KRAS expression. Thespecific amount that is therapeutically effective can be readilydetermined by an ordinary medical practitioner, and may vary dependingon factors known in the art, such as, for example, the type ofpathological processes mediated by KRAS expression, the patient'shistory and age, the stage of pathological processes mediated by KRASexpression, and the administration of other agents that inhibitpathological processes mediated by KRAS expression.

In various embodiments of the present disclosure, the patient is atleast about 1, 3, 6, or 9 months, or 1, 5, 10, 20, 30, 40, 50, 55, 60,65, 70, or 75 years of age. In various embodiments, the patient is nomore than about 1, 3, 6, or 9 months, or 1, 5, 10, 20, 30, 40, 50, 55,60, 65, 70, 75, 80, 90, or 100 years of age. In various embodiments thepatient has a body weight of at least about 5, 10, 15, 20, 30, 40, 50,60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300,320, 340, 360, 380 or 400 lbs. In various embodiments, the patient has abody weight of no more than about 5, 10, 15, 20, 30, 40, 50, 60, 70, 80,90, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340,360, 380 or 400 lbs.

In various embodiments of the present disclosure, the dosage [measuringonly the active ingredient(s)] can be at least about 1, 5, 10, 25, 50,100, 200, 250, 300, 250, 400, 450, 500, 550, 600, 650, 700, 750, 800,850, 900, 950 or 1000 ng, 1, 5, 10, 25, 50, 100, 200, 250, 300, 250,400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000micrograms, 1, 5, 10, 25, 50, 100, 200, 250, 300, 250, 400, 450, 500,550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg. In variousembodiments, the dosage can be no more than about 10, 25, 50, 100, 200,250, 300, 250, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900,950 or 1000 mg. In various embodiments, the dosage can be administeredat least more than once a day, daily, more than once a weekly, weekly,bi-weekly, monthly, and/or every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12months, or a combination thereof.

In various embodiments, the dosage is correlated to the body weight orbody surface area of the individual. The actual dosage level can bevaried to obtain an amount of active agent which is effective for aparticular patient, composition and mode of administration, withoutbeing toxic to the patient. The selected dose will depend on a varietyof pharmacokinetic factors, including the activity of the particularRNAi agent employed, the route of administration, the rate of excretionof the RNAi agent, the duration of the treatment, other drugs, compoundsand/or materials used in combination with the RNAi agent, the age, sex,weight, condition, general health and prior medical history of thepatient, and like factors well known in the medical arts. A physician orveterinarian having ordinary skill in the art can readily determine theeffective amount of the RNAi agent required. A suitable dose will bethat amount which is the lowest dose effective to produce a therapeuticeffect, or a dose low enough to produce a therapeutic effect withoutcausing side effects.

RNAi Agents to KRAS in Combination with Other Therapies

In addition to a therapeutically-effective dosage of one or more RNAiagents to KRAS, the pharmaceutical compositions of the presentdisclosure can comprise or be used in conjunction with an additionaldisease treatment which works synergistically with the RNAi agent.

In addition, many tumors contain mutations in both KRAS and one or moreother genes. For example, some lung cancer or colorectal tumor cells orother types of cancer can have mutations in both KRAS and one or moreof: EGFR, GLUT1, P13K, RAF, and APC. Haigis et al. 2008 Nature Gen. 40:600-608; Karapetis et al. 2008 N. E. J. Med. 359: 1757-1765; and Yun etal. 2009 Science 325: 1555-1559. Effective combination therapy cancomprise a KRAS RNAi agent combined with an agent which targets theother mutated hyper-active or overexpressed protein, or which is anapproved therapy for the cancer type being treated.

RNAi agents to KRAS can thus be effective when used in a regimeninvolving other disease treatments. Some of these treatments are noteffective when the patient has an activating mutation in KRAS. However,the RNAi agent to KRAS can reduce the overall amount of KRAS, improvingthe efficacy of disease treatments which are not effective in thepresence of an activating KRAS mutation.

Furthermore, proliferation, survival and/or apoptosis resistance ofKRAS-defective tumor cells may require another factor such as NF-kappa-Bor I-kappa-B kinase TBK1. Meylan et al. 2009 Nature 462: 104-107; andBarbie et al. 2009 Nature 462: 108-112. Thus, in some embodiments,effective combination therapy can comprise administration of a KRAS RNAiagent and administration (or co-administration) of a treatment whichtargets the other factor (e.g., a siRNA, antibody or small moleculewhich targets NF-kappa-B or TBK1).

Thus, the KRAS RNAi agent can be used in a combination therapy alongwith any other therapeutic composition or method or therapy, includingthose which specifically target another factor, or which are otherwiseknown to be effective in treatment of a KRAS-related disease.

In the treatment of these KRAS-related diseases, the RNAi agent(s) andadditional disease treatment(s) can be administered in any order,simultaneously or sequentially, or in multiple doses over time.Administration of the RNAi agent and the additional treatment can be,for example, simultaneous, concurrent, separate or sequential.

Simultaneous administration may, e.g., take place in the form of onefixed combination with two or more active ingredients, or bysimultaneously administering two or more active ingredients that areformulated independently. Sequential use (administration) preferablymeans administration of one (or more) components of a combination at onetime point, other components at a different time point, that is, in achronically staggered manner, preferably such that the combination showsmore efficiency than the single compounds administered independently(especially showing synergism). Separate use (administration) preferablymeans administration of the components of the combination independentlyof each other at different time points, preferably meaning that thecomponents (a) and (b) are administered such that no overlap ofsignificant measurable blood levels of both compounds are present in anoverlapping manner (at the same time).

Also combinations of two or more of sequential, separate andsimultaneous administration are possible, preferably such that thecombination component-drugs show a joint therapeutic effect that exceedsthe effect found when the combination component-drugs are usedindependently at time intervals so large that no mutual effect on theirtherapeutic efficiency can be found, a synergistic effect beingespecially preferred.

The term “delay of progression” as used herein means administration ofthe combination to patients being in a pre-stage or in an early phase,of the first manifestation or a relapse of the disease to be treated, inwhich patients, e.g., a pre-form of the corresponding disease isdiagnosed or which patients are in a condition, e.g., during a medicaltreatment or a condition resulting from an accident, under which it islikely that a corresponding disease will develop.

“Jointly therapeutically active” or “joint therapeutic effect” meansthat the compounds may be given separately (in a chronically staggeredmanner, especially a sequence-specific manner) in such time intervalsthat they preferably, in the warm-blooded animal, especially human, tobe treated, still show a (preferably synergistic) interaction (jointtherapeutic effect). Whether this is the case, can inter alia bedetermined by following the blood levels, showing that both compoundsare present in the blood of the human to be treated at least duringcertain time intervals.

The present disclosure thus encompasses a combination therapy comprisingboth a KRAS RNAi agent and one or more additional therapies forKRAS-related diseases known in the art.

The use of known treatments for any of KRAS-related diseases is withinthe capabilities of one of ordinary skill in the art. Any suchadditional treatment can be used in conjunction with a RNAi agent toKRAS.

The dosages of the additional treatments and RNAi agents can be easilydetermined by one of ordinary skill in the art, and as described herein.

Embodiments Comprising One or More Efficacious RNAi Agents to KRAS

In various embodiments of the present disclosure, the present disclosurecomprises a RNAi agent demonstrating at least about 40, 50, 60, 70, 80,90 or 95% knockdown (KD) (i.e., no more than about 60, 50, 40, 30, 20,10, or 5% residual gene activity, respectively) of the KRAS gene at anin vitro concentration of 10 or 0.1 nM as assayed in RKO cells.

In various embodiments of the present disclosure, the compositioncomprises one or more RNAi agents capable of a Fold-Change at 10 nM at24 hr of <0.05, <0.10, <0.20, <0.30, <0.40 (indicating a KRAS geneknock-down of at least 95, 90, 80, 70, or 60%, respectively, at aconcentration of 10 nM at 24 hrs in RKO cells). RNAi agents capable ofthese levels of activity are disclosed in the Tables herein.

Embodiments Comprising One or More Efficacious RNAi Agents to KRAS

In various embodiments of the present disclosure, the compositioncomprises one or more RNAi agents capable of a Fold-Change at 0.1 nM at120 hr of <0.30, <0.20, or <0.10 (indicating a KRAS gene knock-down ofat least 70, 80, or 90%, respectively, at a concentration of 0.1 nM at120 hrs in RKO cells). RNAi agents capable of these levels of activityare disclosed in the Tables herein.

Various Embodiments Comprising One or More RNAi Agents to KRAS with LowEC50

In various embodiments of the present disclosure, the compositioncomprises one or more RNAi agents capable of mediating a 50% geneknockdown (EC50) of KRAS at a low concentration in RKO cells. For manyof the RNAi agents listed herein, an estimated EC50 is calculated. Cellsare treated at 10 nM, 1 nM, 0.1 nM, 0.01 nM, and 0.001 nM of RNAi agent,and the data fit to a curve. The indicated EC50 is an estimated EC50calculated from available data that is expected to give 50% geneknock-down of KRAS in RKO cells. In various embodiments of the presentdisclosure, the composition comprises one or more RNAi agents capable ofmediating a 50% gene knockdown (EC50) at 100, 75, 50, 25, 10, 5, 2.5, 1,0.75, 0.5, 0.25, 0.2, 0.12, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04,0.03, or 0.02 nM or less in RKO cells. RNAi agents capable of theselevels of activity are disclosed in the Tables herein.

Specific Embodiments of RNAi Agents to KRAS

In one embodiment, the present disclosure pertains to: a compositioncomprising any one or more of: a RNAi agent comprising a sense strandand an anti-sense strand, wherein the anti-sense strand comprises atleast 15 contiguous nucleotides differing by 0, 1, 2, or 3 nucleotidesfrom the anti-sense strand of: any RNAi agent from any of Tables 1 to 6and modified or unmodified variants thereof.

In one embodiment, the composition comprises any one or more of: a RNAiagent comprising a sense strand and an anti-sense strand, wherein theanti-sense strand comprises at least 15 contiguous nucleotides differingby 0 nucleotides from the anti-sense strand of any RNAi agent from anyof Tables 1 to 6, and modified and unmodified variants thereof.

In one embodiment, the present disclosure pertains to a compositioncomprising any one or more of: any RNAi agent from any of Tables 1 to 6,and modified and unmodified variants thereof.

In one embodiment, the present disclosure pertains to a compositioncomprising any one or more of: a RNAi agent comprising an anti-sensestrand comprising the sequence of the anti-sense strand of any RNAiagent from any of Tables 1 to 6, and modified and unmodified variantsthereof.

In one embodiment, the present disclosure pertains to a compositioncomprising any one or more of: a RNAi agent comprises an anti-sensestrand consisting of the sequence of the anti-sense strand of any RNAiagent from any of Tables 1 to 6, and modified and unmodified variantsthereof.

In one embodiment, the present disclosure pertains to a compositioncomprising any one or more of: a RNAi agent comprising a first strandand a second strand, wherein the sequence of the first strand is thesecond of the first strand of any RNAi agent from any of Tables 1 to 6,and modified and unmodified variants thereof.

In one embodiment, the present disclosure pertains to a compositioncomprising any one or more of: a RNAi agent comprising a first and asecond strand, wherein the sequences of the first and the second strandare the sequences of the first and second strand of any RNAi agent fromany of Tables 1 to 6, and modified and unmodified variants thereof.

In one embodiment, the present disclosure pertains to a compositioncomprising any one or more of: a RNAi agent comprising a first strandand a second strand, wherein the sequence of the first strand is thesecond of the first strand of any RNAi agent from any of Tables 1 to 6,and modified and unmodified variants thereof, wherein the first and/orsecond strand further comprise up to about 20 additional nucleotides.

Specific embodiments of RNAi agents to KRAS

In one embodiment, the present disclosure pertains to: a compositioncomprising any one or more of: a RNAi agent comprising a first strandand a second strand, wherein the first strand comprises at least 15contiguous nucleotides differing by 0, 1, 2, or 3 nucleotides from thefirst strand of: any RNAi agent from any of Tables 1 to 6 or modified orunmodified variants thereof.

In one embodiment, the present disclosure pertains to: a compositioncomprising any one or more of: a RNAi agent comprising a first strandand a second strand, wherein the first strand comprises at least 15contiguous nucleotides from the first strand of any RNAi agent from anyof Tables 1 to 6, or modified and unmodified variants thereof.

In one embodiment, the present disclosure pertains to a compositioncomprising any one or more of: a RNAi agent comprising a first strandand a second strand, wherein the sequence of the first strand is thesequence of a first strand of any RNAi agent from any of Tables 1 to 6,or modified and unmodified variants thereof.

In one embodiment, the present disclosure pertains to a compositioncomprising any one or more of: a RNAi agent comprising a first and asecond strand, wherein the sequences of the first and/or second strandscomprise the sequences of a first and/or second strands of any RNAiagent from any of Tables 1 to 6, or modified and unmodified variantsthereof.

In one embodiment, the present disclosure pertains to a compositioncomprising any one or more of: a RNAi agent comprising a first and asecond strand, wherein the sequences of the first and the second strandare the sequences of the first and second strand of any RNAi agent fromany of Tables 1 to 6, or modified and unmodified variants thereof.

In one embodiment, the present disclosure pertains to a compositioncomprising any one or more of: a RNAi agent comprising a first and asecond strand, wherein the sequence of the first and/or second strand isthe sequence of a first and/or second strand of any RNAi agent from anyof Tables 1 to 6, or modified and unmodified variants thereof, whereinthe first and/or second strand further comprise up to about 20additional nucleotides.

Specific embodiments comprising at least 15 contiguous nucleotidesdiffering from 0 to 3 nt from RNAi agents disclosed herein

In one embodiment, the present disclosure pertains to: a compositioncomprising any one or more of: a RNAi agent comprising a first and asecond strand, wherein the first strand comprises at least 15 contiguousnucleotides (nt) differing by 0, 1, 2, or 3 nt from a first strand of:any RNAi agent from any of Tables 1 to 6 or modified or unmodifiedvariants thereof.

Thus, in various embodiments, the present disclosure pertains to acomposition comprising any one or more of the following:

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35523.3 (SEQ ID NO: 428), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35529.1 (SEQ ID NO: 429), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35535.4 (SEQ ID NO: 430), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35541.4 (SEQ ID NO: 431), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35547.4 (SEQ ID NO: 432), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35553.4 (SEQ ID NO: 433), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35559.4 (SEQ ID NO: 434), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35565.4 (SEQ ID NO: 435), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35524.4 (SEQ ID NO: 436), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35530.4 (SEQ ID NO: 437), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35536.4 (SEQ ID NO: 438), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35542.4 (SEQ ID NO: 439), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35548.4 (SEQ ID NO: 440), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35554.4 (SEQ ID NO: 441), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35560.2 (SEQ ID NO: 442), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35566.4 (SEQ ID NO: 443), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35525.2 (SEQ ID NO: 444), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35531.4 (SEQ ID NO: 445), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35537.4 (SEQ ID NO: 446), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35543.2 (SEQ ID NO: 447), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35549.4 (SEQ ID NO: 448), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35555.4 (SEQ ID NO: 449), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35561.4 (SEQ ID NO: 450), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35567.4 (SEQ ID NO: 451), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35526.4 (SEQ ID NO: 452), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35532.4 (SEQ ID NO: 453), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35538.4 (SEQ ID NO: 454), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35544.4 (SEQ ID NO: 455), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35550.4 (SEQ ID NO: 456), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35556.4 (SEQ ID NO: 457), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35562.4 (SEQ ID NO: 458), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35568.4 (SEQ ID NO: 459), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35527.4 (SEQ ID NO: 460), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35533.4 (SEQ ID NO: 461), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35539.4 (SEQ ID NO: 462), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35545.4 (SEQ ID NO: 463), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35551.4 (SEQ ID NO: 464), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35563.4 (SEQ ID NO: 465), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35528.4 (SEQ ID NO: 466), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35540.4 (SEQ ID NO: 467), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35546.4 (SEQ ID NO: 468), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35552.4 (SEQ ID NO: 469), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35558.4 (SEQ ID NO: 470), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35564.4 (SEQ ID NO: 471), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35570.4 (SEQ ID NO: 472), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35571.4 (SEQ ID NO: 473), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35577.4 (SEQ ID NO: 474), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35583.4 (SEQ ID NO: 475), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35589.4 (SEQ ID NO: 476), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35595.4 (SEQ ID NO: 477), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35601.4 (SEQ ID NO: 478), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35607.4 (SEQ ID NO: 479), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35613.4 (SEQ ID NO: 480), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35572.4 (SEQ ID NO: 481), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35578.4 (SEQ ID NO: 482), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35584.4 (SEQ ID NO: 483), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35590.4 (SEQ ID NO: 484), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35596.4 (SEQ ID NO: 485), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35602.4 (SEQ ID NO: 486), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35608.4 (SEQ ID NO: 487), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35614.4 (SEQ ID NO: 488), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35573.4 (SEQ ID NO: 489), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35579.4 (SEQ ID NO: 490), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35585.4 (SEQ ID NO: 491), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35591.4 (SEQ ID NO: 492), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35597.4 (SEQ ID NO: 493), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35603.4 (SEQ ID NO: 494), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35609.4 (SEQ ID NO: 495), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35615.4 (SEQ ID NO: 496), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35574.4 (SEQ ID NO: 497), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35580.1 (SEQ ID NO: 498), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35586.4 (SEQ ID NO: 499), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35592.4 (SEQ ID NO: 500), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35598.4 (SEQ ID NO: 501), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35604.4 (SEQ ID NO: 502), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35610.4 (SEQ ID NO: 503), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35616.4 (SEQ ID NO: 504), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35575.4 (SEQ ID NO: 505), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35581.4 (SEQ ID NO: 506), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35587.4 (SEQ ID NO: 507), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35593.4 (SEQ ID NO: 508), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35599.4 (SEQ ID NO: 509), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35605.4 (SEQ ID NO: 510), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35611.4 (SEQ ID NO: 511), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35617.4 (SEQ ID NO: 512), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35576.4 (SEQ ID NO: 513), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35588.4 (SEQ ID NO: 514), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35667.1 (SEQ ID NO: 515), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35673.1 (SEQ ID NO: 516), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35679.1 (SEQ ID NO: 517), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35685.1 (SEQ ID NO: 518), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35691.1 (SEQ ID NO: 519), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35557.1 (SEQ ID NO: 520), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35618.1 (SEQ ID NO: 521), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35569.1 (SEQ ID NO: 522), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35534.1 (SEQ ID NO: 523), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35582.1 (SEQ ID NO: 524), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35594.1 (SEQ ID NO: 525), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35600.1 (SEQ ID NO: 526), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35606.1 (SEQ ID NO: 527), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35612.1 (SEQ ID NO: 528), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38127.1 (SEQ ID NO: 529), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38133.1 (SEQ ID NO: 530), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38139.1 (SEQ ID NO: 531), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38145.1 (SEQ ID NO: 532), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38151.1 (SEQ ID NO: 533), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38157.1 (SEQ ID NO: 534), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38163.1 (SEQ ID NO: 535), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38169.1 (SEQ ID NO: 536), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38128.1 (SEQ ID NO: 537), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38134.1 (SEQ ID NO: 538), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38140.1 (SEQ ID NO: 539), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38146.1 (SEQ ID NO: 540), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38152.1 (SEQ ID NO: 541), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38158.1 (SEQ ID NO: 542), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38164.1 (SEQ ID NO: 543), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38170.1 (SEQ ID NO: 544), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38129.1 (SEQ ID NO: 545), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38135.1 (SEQ ID NO: 546), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38141.1 (SEQ ID NO: 547), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38147.1 (SEQ ID NO: 548), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38153.1 (SEQ ID NO: 549), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38159.1 (SEQ ID NO: 550), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38165.1 (SEQ ID NO: 551), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38171.1 (SEQ ID NO: 552), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38130.1 (SEQ ID NO: 553), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38136.1 (SEQ ID NO: 554), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38142.1 (SEQ ID NO: 555), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38148.1 (SEQ ID NO: 556), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38154.1 (SEQ ID NO: 557), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38160.1 (SEQ ID NO: 558), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38166.1 (SEQ ID NO: 559), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38172.1 (SEQ ID NO: 560), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38131.1 (SEQ ID NO: 561), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38137.1 (SEQ ID NO: 562), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38143.1 (SEQ ID NO: 563), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38149.1 (SEQ ID NO: 564), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38155.1 (SEQ ID NO: 565), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38161.1 (SEQ ID NO: 566), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38167.1 (SEQ ID NO: 567), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38173.1 (SEQ ID NO: 568), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38132.1 (SEQ ID NO: 569), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38138.1 (SEQ ID NO: 570), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38144.1 (SEQ ID NO: 571), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38150.1 (SEQ ID NO: 572), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38156.1 (SEQ ID NO: 573), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38162.1 (SEQ ID NO: 574), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38168.1 (SEQ ID NO: 575), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38174.1 (SEQ ID NO: 576), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39683.1 (SEQ ID NO: 577), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39689.1 (SEQ ID NO: 578), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39695.1 (SEQ ID NO: 579), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39701.1 (SEQ ID NO: 580), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39707.1 (SEQ ID NO: 581), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39713.1 (SEQ ID NO: 582), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39719.1 (SEQ ID NO: 583), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39725.1 (SEQ ID NO: 584), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39684.1 (SEQ ID NO: 585), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39690.1 (SEQ ID NO: 586), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39696.1 (SEQ ID NO: 587), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39702.1 (SEQ ID NO: 588), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39708.1 (SEQ ID NO: 589), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39714.1 (SEQ ID NO: 590), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39720.1 (SEQ ID NO: 591), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39726.1 (SEQ ID NO: 592), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39685.1 (SEQ ID NO: 593), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39691.1 (SEQ ID NO: 594), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39697.1 (SEQ ID NO: 595), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39703.1 (SEQ ID NO: 596), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39709.1 (SEQ ID NO: 597), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39715.1 (SEQ ID NO: 598), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39721.1 (SEQ ID NO: 599), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39727.1 (SEQ ID NO: 600), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39686.1 (SEQ ID NO: 601), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39692.1 (SEQ ID NO: 602), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39698.1 (SEQ ID NO: 603), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39704.1 (SEQ ID NO: 604), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39710.1 (SEQ ID NO: 605), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39716.1 (SEQ ID NO: 606), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39722.1 (SEQ ID NO: 607), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39728.1 (SEQ ID NO: 608), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39687.1 (SEQ ID NO: 609), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39693.1 (SEQ ID NO: 610), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39699.1 (SEQ ID NO: 611), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39705.1 (SEQ ID NO: 612), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39711.1 (SEQ ID NO: 613), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39717.1 (SEQ ID NO: 614), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39723.1 (SEQ ID NO: 615), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39729.1 (SEQ ID NO: 616), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39688.1 (SEQ ID NO: 617), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39694.1 (SEQ ID NO: 618), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39700.1 (SEQ ID NO: 619), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39706.1 (SEQ ID NO: 620), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39712.1 (SEQ ID NO: 621), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39718.1 (SEQ ID NO: 622), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39724.1 (SEQ ID NO: 623), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39730.1 (SEQ ID NO: 624), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39736.1 (SEQ ID NO: 625), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39742.1 (SEQ ID NO: 626), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39748.1 (SEQ ID NO: 627), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39754.1 (SEQ ID NO: 628), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39760.1 (SEQ ID NO: 629), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39766.1 (SEQ ID NO: 630), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39772.1 (SEQ ID NO: 631), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39731.1 (SEQ ID NO: 632), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39737.1 (SEQ ID NO: 633), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39743.1 (SEQ ID NO: 634), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39749.1 (SEQ ID NO: 635), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39755.1 (SEQ ID NO: 636), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39761.1 (SEQ ID NO: 637), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39767.1 (SEQ ID NO: 638), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39773.1 (SEQ ID NO: 639), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39732.1 (SEQ ID NO: 640), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39738.1 (SEQ ID NO: 641), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39744.1 (SEQ ID NO: 642), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39750.1 (SEQ ID NO: 643), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39756.1 (SEQ ID NO: 644), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39762.1 (SEQ ID NO: 645), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39768.1 (SEQ ID NO: 646), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39774.1 (SEQ ID NO: 647), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39733.1 (SEQ ID NO: 648), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39739.1 (SEQ ID NO: 649), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39745.1 (SEQ ID NO: 650), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39751.1 (SEQ ID NO: 651), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39757.1 (SEQ ID NO: 652), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39763.1 (SEQ ID NO: 653), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39769.1 (SEQ ID NO: 654), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39775.1 (SEQ ID NO: 655), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39734.1 (SEQ ID NO: 656), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39740.1 (SEQ ID NO: 657), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39746.1 (SEQ ID NO: 658), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39752.1 (SEQ ID NO: 659), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39758.1 (SEQ ID NO: 660), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39764.1 (SEQ ID NO: 661), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39770.1 (SEQ ID NO: 662), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39776.1 (SEQ ID NO: 663), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39735.1 (SEQ ID NO: 664), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39741.1 (SEQ ID NO: 665), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39747.1 (SEQ ID NO: 666), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39753.1 (SEQ ID NO: 667), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39759.1 (SEQ ID NO: 668), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39765.1 (SEQ ID NO: 669), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39771.1 (SEQ ID NO: 670), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39778.1 (SEQ ID NO: 671), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39784.1 (SEQ ID NO: 672), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39790.1 (SEQ ID NO: 673), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39796.1 (SEQ ID NO: 674), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39802.1 (SEQ ID NO: 675), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39808.1 (SEQ ID NO: 676), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39814.1 (SEQ ID NO: 677), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39820.1 (SEQ ID NO: 678), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39779.1 (SEQ ID NO: 679), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39785.1 (SEQ ID NO: 680), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39791.1 (SEQ ID NO: 681), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39797.1 (SEQ ID NO: 682), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39803.1 (SEQ ID NO: 683), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39809.1 (SEQ ID NO: 684), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39815.1 (SEQ ID NO: 685), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39821.1 (SEQ ID NO: 686), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39780.1 (SEQ ID NO: 687), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39786.1 (SEQ ID NO: 688), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39792.1 (SEQ ID NO: 689), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39798.1 (SEQ ID NO: 690), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39804.1 (SEQ ID NO: 691), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39810.1 (SEQ ID NO: 692), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39816.1 (SEQ ID NO: 693), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39822.1 (SEQ ID NO: 694), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39781.1 (SEQ ID NO: 695), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39787.1 (SEQ ID NO: 696), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39793.1 (SEQ ID NO: 697), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39799.1 (SEQ ID NO: 698), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39805.1 (SEQ ID NO: 699), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39811.1 (SEQ ID NO: 700), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39817.1 (SEQ ID NO: 701), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39823.1 (SEQ ID NO: 702), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39782.1 (SEQ ID NO: 703), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39788.1 (SEQ ID NO: 704), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39794.1 (SEQ ID NO: 705), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39800.1 (SEQ ID NO: 706), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39806.1 (SEQ ID NO: 707), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39812.1 (SEQ ID NO: 708), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39818.1 (SEQ ID NO: 709), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39824.1 (SEQ ID NO: 710), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39783.1 (SEQ ID NO: 711), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39789.1 (SEQ ID NO: 712), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39795.1 (SEQ ID NO: 713), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39801.1 (SEQ ID NO: 714), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39807.1 (SEQ ID NO: 715), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39813.1 (SEQ ID NO: 716), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39819.1 (SEQ ID NO: 717), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39825.1 (SEQ ID NO: 718), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39831.1 (SEQ ID NO: 719), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39837.1 (SEQ ID NO: 720), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39843.1 (SEQ ID NO: 721), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39849.1 (SEQ ID NO: 722), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39855.1 (SEQ ID NO: 723), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39861.1 (SEQ ID NO: 724), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39867.1 (SEQ ID NO: 725), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39826.1 (SEQ ID NO: 726), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39832.1 (SEQ ID NO: 727), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39838.1 (SEQ ID NO: 728), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39844.1 (SEQ ID NO: 729), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39850.1 (SEQ ID NO: 730), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39856.1 (SEQ ID NO: 731), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39862.1 (SEQ ID NO: 732), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39868.1 (SEQ ID NO: 733), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39827.1 (SEQ ID NO: 734), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39833.1 (SEQ ID NO: 735), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39839.1 (SEQ ID NO: 736), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39845.1 (SEQ ID NO: 737), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39851.1 (SEQ ID NO: 738), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39857.1 (SEQ ID NO: 739), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39863.1 (SEQ ID NO: 740), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39869.1 (SEQ ID NO: 741), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39828.1 (SEQ ID NO: 742), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39834.1 (SEQ ID NO: 743), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39840.1 (SEQ ID NO: 744), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39846.1 (SEQ ID NO: 745), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39852.1 (SEQ ID NO: 746), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39858.1 (SEQ ID NO: 747), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39864.1 (SEQ ID NO: 748), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39870.1 (SEQ ID NO: 749), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39829.1 (SEQ ID NO: 750), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39835.1 (SEQ ID NO: 751), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39841.1 (SEQ ID NO: 752), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39853.1 (SEQ ID NO: 753), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39859.1 (SEQ ID NO: 754), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39865.1 (SEQ ID NO: 755), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39871.1 (SEQ ID NO: 756), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39830.1 (SEQ ID NO: 757), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39836.1 (SEQ ID NO: 758), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39842.1 (SEQ ID NO: 759), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39848.1 (SEQ ID NO: 760), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39854.1 (SEQ ID NO: 761), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39860.1 (SEQ ID NO: 762), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39866.1 (SEQ ID NO: 763), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39992.1 (SEQ ID NO: 764), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39998.1 (SEQ ID NO: 765), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40004.1 (SEQ ID NO: 766), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40010.1 (SEQ ID NO: 767), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40016.1 (SEQ ID NO: 768), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40022.1 (SEQ ID NO: 769), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40028.1 (SEQ ID NO: 770), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40034.1 (SEQ ID NO: 771), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39999.1 (SEQ ID NO: 772), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40005.1 (SEQ ID NO: 773), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40011.1 (SEQ ID NO: 774), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40017.1 (SEQ ID NO: 775), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40029.1 (SEQ ID NO: 776), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40035.1 (SEQ ID NO: 777), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39994.1 (SEQ ID NO: 778), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40000.1 (SEQ ID NO: 779), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40006.1 (SEQ ID NO: 780), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40012.1 (SEQ ID NO: 781), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40018.1 (SEQ ID NO: 782), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40024.1 (SEQ ID NO: 783), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40030.1 (SEQ ID NO: 784), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40036.1 (SEQ ID NO: 785), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39995.1 (SEQ ID NO: 786), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40001.1 (SEQ ID NO: 787), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40007.1 (SEQ ID NO: 788), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40013.1 (SEQ ID NO: 789), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40019.1 (SEQ ID NO: 790), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40025.1 (SEQ ID NO: 791), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40031.1 (SEQ ID NO: 792), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40037.1 (SEQ ID NO: 793), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39996.1 (SEQ ID NO: 794), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40002.1 (SEQ ID NO: 795), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40008.1 (SEQ ID NO: 796), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40014.1 (SEQ ID NO: 797), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40020.1 (SEQ ID NO: 798), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40026.1 (SEQ ID NO: 799), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40032.1 (SEQ ID NO: 800), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40038.1 (SEQ ID NO: 801), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39997.1 (SEQ ID NO: 802), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40009.1 (SEQ ID NO: 803), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40015.1 (SEQ ID NO: 804), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40021.1 (SEQ ID NO: 805), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40027.1 (SEQ ID NO: 806), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40033.1 (SEQ ID NO: 807), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40039.1 (SEQ ID NO: 808), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40045.1 (SEQ ID NO: 809), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40051.1 (SEQ ID NO: 810), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40057.1 (SEQ ID NO: 811), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40063.1 (SEQ ID NO: 812), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40069.1 (SEQ ID NO: 813), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40075.1 (SEQ ID NO: 814), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40081.1 (SEQ ID NO: 815), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40040.1 (SEQ ID NO: 816), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40046.1 (SEQ ID NO: 817), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40052.1 (SEQ ID NO: 818), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40058.1 (SEQ ID NO: 819), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40064.1 (SEQ ID NO: 820), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40070.1 (SEQ ID NO: 821), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40076.1 (SEQ ID NO: 822), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40082.1 (SEQ ID NO: 823), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40041.1 (SEQ ID NO: 824), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40047.1 (SEQ ID NO: 825), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40053.1 (SEQ ID NO: 826), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40059.1 (SEQ ID NO: 827), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40065.1 (SEQ ID NO: 828), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40071.1 (SEQ ID NO: 829), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40077.1 (SEQ ID NO: 830), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40083.1 (SEQ ID NO: 831), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40042.1 (SEQ ID NO: 832), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40048.1 (SEQ ID NO: 833), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40054.1 (SEQ ID NO: 834), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40060.1 (SEQ ID NO: 835), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40066.1 (SEQ ID NO: 836), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40072.1 (SEQ ID NO: 837), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40078.1 (SEQ ID NO: 838), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40084.1 (SEQ ID NO: 839), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40043.1 (SEQ ID NO: 840), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40049.1 (SEQ ID NO: 841), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40055.1 (SEQ ID NO: 842), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40061.1 (SEQ ID NO: 843), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40067.1 (SEQ ID NO: 844), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40073.1 (SEQ ID NO: 845), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40079.1 (SEQ ID NO: 846), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40085.1 (SEQ ID NO: 847), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40044.1 (SEQ ID NO: 848), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40050.1 (SEQ ID NO: 849), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40056.1 (SEQ ID NO: 850), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40062.1 (SEQ ID NO: 851), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40068.1 (SEQ ID NO: 852), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40074.1 (SEQ ID NO: 853), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40080.1 (SEQ ID NO: 854), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39720.1 (SEQ ID NO: 1754), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39706.1 (SEQ ID NO: 1755), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39712.1 (SEQ ID NO: 1756), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39760.1 (SEQ ID NO: 1757), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39732.1 (SEQ ID NO: 1758), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35541.4 (SEQ ID NO: 1759), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39735.1 or hs_KRAS_(—)321_A22S26 (SEQ ID NO:1760), or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39741.1, or modified or unmodified variantsthereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: hs_KRAS_(—) 322_A22S26 (SEQ ID NO: 1761), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39778.1 (SEQ ID NO: 1762), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39790.1 (SEQ ID NO: 1763), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39822.1 (SEQ ID NO: 1764), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35609.4 (SEQ ID NO: 1765), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35581.4 (SEQ ID NO: 1766), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39845.1 (SEQ ID NO: 1767), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39858.1 (SEQ ID NO: 1768), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39870.1 (SEQ ID NO: 1769), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35576.4 (SEQ ID NO: 1770), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35588.4 (SEQ ID NO: 1771), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35600.1 (SEQ ID NO: 1772), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-35606.1 (SEQ ID NO: 1773), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38151.1 (SEQ ID NO: 1774), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38163.1 (SEQ ID NO: 1775), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-39999.1 (SEQ ID NO: 1776), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38159.1 or hs_KRAS_(—)528_A22S26 (SEQ ID NO:1777), or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38130.1 or hs_KRAS_(—)531_A22S26 (SEQ ID NO:1778), or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38136.1 (SEQ ID NO: 1779), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40036.1 (SEQ ID NO: 1780), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40008.1 (SEQ ID NO: 1781), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40021.1 (SEQ ID NO: 1782), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40077.1 (SEQ ID NO: 1783), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40072.1 (SEQ ID NO: 1784), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40061.1 (SEQ ID NO: 1785), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-40068.1 (SEQ ID NO: 1786), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38131.1 (SEQ ID NO: 1787), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: AD-38167.1 (SEQ ID NO: 1788), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: hs_KRAS 1273_A22S26 (SEQ ID NO: 1789), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: hs_KRAS 2892_A37S26 (SEQ ID NO: 1790), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein the firststrand comprises at least 15 contiguous nt differing by 0, 1, 2, or 3 ntfrom a first strand of: hs_KRAS 4731_A22S26 (SEQ ID NO: 1791), or amodified or unmodified variant thereof.

Specific embodiments comprising at least 15 contiguous nucleotides ofany RNAi agent disclosed herein

In one embodiment, the present disclosure pertains to: a compositioncomprising any one or more of: a RNAi agent comprising a first strandand a second strand, wherein the first strand comprises at least 15contiguous nucleotides (differing by 0 nucleotides) from a first strandof: any RNAi agent from any of Tables 1 to 6 or modified or unmodifiedvariants thereof.

Thus, in various embodiments, the present disclosure pertains to acomposition comprising any one or more of the following:

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35523.3 (SEQ ID NO: 428), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35529.1 (SEQ ID NO: 429), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35535.4 (SEQ ID NO: 430), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35541.4 (SEQ ID NO: 431), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35547.4 (SEQ ID NO: 432), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35553.4 (SEQ ID NO: 433), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35559.4 (SEQ ID NO: 434), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35565.4 (SEQ ID NO: 435), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35524.4 (SEQ ID NO: 436), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35530.4 (SEQ ID NO: 437), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35536.4 (SEQ ID NO: 438), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35542.4 (SEQ ID NO: 439), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35548.4 (SEQ ID NO: 440), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35554.4 (SEQ ID NO: 441), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35560.2 (SEQ ID NO: 442), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35566.4 (SEQ ID NO: 443), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35525.2 (SEQ ID NO: 444), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35531.4 (SEQ ID NO: 445), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35537.4 (SEQ ID NO: 446), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35543.2 (SEQ ID NO: 447), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35549.4 (SEQ ID NO: 448), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35555.4 (SEQ ID NO: 449), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35561.4 (SEQ ID NO: 450), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35567.4 (SEQ ID NO: 451), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35526.4 (SEQ ID NO: 452), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35532.4 (SEQ ID NO: 453), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35538.4 (SEQ ID NO: 454), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35544.4 (SEQ ID NO: 455), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35550.4 (SEQ ID NO: 456), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35556.4 (SEQ ID NO: 457), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35562.4 (SEQ ID NO: 458), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35568.4 (SEQ ID NO: 459), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35527.4 (SEQ ID NO: 460), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35533.4 (SEQ ID NO: 461),

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35539.4 (SEQ ID NO: 462), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35545.4 (SEQ ID NO: 463), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35551.4 (SEQ ID NO: 464), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35563.4 (SEQ ID NO: 465), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35528.4 (SEQ ID NO: 466), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35540.4 (SEQ ID NO: 467), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35546.4 (SEQ ID NO: 468), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35552.4 (SEQ ID NO: 469), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35558.4 (SEQ ID NO: 470), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35564.4 (SEQ ID NO: 471), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35570.4 (SEQ ID NO: 472), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35571.4 (SEQ ID NO: 473), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35577.4 (SEQ ID NO: 474), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35583.4 (SEQ ID NO: 475), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35589.4 (SEQ ID NO: 476), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35595.4 (SEQ ID NO: 477), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35601.4 (SEQ ID NO: 478), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35607.4 (SEQ ID NO: 479), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35613.4 (SEQ ID NO: 480), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35572.4 (SEQ ID NO: 481), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35578.4 (SEQ ID NO: 482), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35584.4 (SEQ ID NO: 483), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35590.4 (SEQ ID NO: 484), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35596.4 (SEQ ID NO: 485), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35602.4 (SEQ ID NO: 486), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35608.4 (SEQ ID NO: 487), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35614.4 (SEQ ID NO: 488), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35573.4 (SEQ ID NO: 489), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35579.4 (SEQ ID NO: 490), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35585.4 (SEQ ID NO: 491), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35591.4 (SEQ ID NO: 492), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35597.4 (SEQ ID NO: 493), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35603.4 (SEQ ID NO: 494), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35609.4 (SEQ ID NO: 495), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35615.4 (SEQ ID NO: 496), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35574.4 (SEQ ID NO: 497), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35580.1 (SEQ ID NO: 498), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35586.4 (SEQ ID NO: 499), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35592.4 (SEQ ID NO: 500), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35598.4 (SEQ ID NO: 501), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35604.4 (SEQ ID NO: 502),

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35610.4 (SEQ ID NO: 503), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35616.4 (SEQ ID NO: 504), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35575.4 (SEQ ID NO: 505), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35581.4 (SEQ ID NO: 506), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35587.4 (SEQ ID NO: 507), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35593.4 (SEQ ID NO: 508), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35599.4 (SEQ ID NO: 509), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35605.4 (SEQ ID NO: 510), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35611.4 (SEQ ID NO: 511), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35617.4 (SEQ ID NO: 512), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35576.4 (SEQ ID NO: 513), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35588.4 (SEQ ID NO: 514), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35667.1 (SEQ ID NO: 515), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35673.1 (SEQ ID NO: 516), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35679.1 (SEQ ID NO: 517), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35685.1 (SEQ ID NO: 518), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35691.1 (SEQ ID NO: 519), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35557.1 (SEQ ID NO: 520), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35618.1 (SEQ ID NO: 521), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35569.1 (SEQ ID NO: 522), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35534.1 (SEQ ID NO: 523), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35582.1 (SEQ ID NO: 524), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35594.1 (SEQ ID NO: 525), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35600.1 (SEQ ID NO: 526), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35606.1 (SEQ ID NO: 527), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35612.1 (SEQ ID NO: 528), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38127.1 (SEQ ID NO: 529), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38133.1 (SEQ ID NO: 530), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38139.1 (SEQ ID NO: 531), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38145.1 (SEQ ID NO: 532), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38151.1 (SEQ ID NO: 533), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38157.1 (SEQ ID NO: 534), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38163.1 (SEQ ID NO: 535), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38169.1 (SEQ ID NO: 536), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38128.1 (SEQ ID NO: 537), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38134.1 (SEQ ID NO: 538), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38140.1 (SEQ ID NO: 539), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38146.1 (SEQ ID NO: 540), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38152.1 (SEQ ID NO: 541), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38158.1 (SEQ ID NO: 542), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38164.1 (SEQ ID NO: 543),

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38170.1 (SEQ ID NO: 544), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38129.1 (SEQ ID NO: 545), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38135.1 (SEQ ID NO: 546), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38141.1 (SEQ ID NO: 547), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38147.1 (SEQ ID NO: 548), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38153.1 (SEQ ID NO: 549), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38159.1 (SEQ ID NO: 550), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38165.1 (SEQ ID NO: 551), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38171.1 (SEQ ID NO: 552), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38130.1 (SEQ ID NO: 553), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38136.1 (SEQ ID NO: 554), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38142.1 (SEQ ID NO: 555), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38148.1 (SEQ ID NO: 556), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38154.1 (SEQ ID NO: 557), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38160.1 (SEQ ID NO: 558), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38166.1 (SEQ ID NO: 559), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38172.1 (SEQ ID NO: 560), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38131.1 (SEQ ID NO: 561), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38137.1 (SEQ ID NO: 562), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38143.1 (SEQ ID NO: 563), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38149.1 (SEQ ID NO: 564), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38155.1 (SEQ ID NO: 565), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38161.1 (SEQ ID NO: 566), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38167.1 (SEQ ID NO: 567), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38173.1 (SEQ ID NO: 568), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38132.1 (SEQ ID NO: 569), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38138.1 (SEQ ID NO: 570), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38144.1 (SEQ ID NO: 571), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38150.1 (SEQ ID NO: 572), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38156.1 (SEQ ID NO: 573), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38162.1 (SEQ ID NO: 574), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38168.1 (SEQ ID NO: 575), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38174.1 (SEQ ID NO: 576), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39683.1 (SEQ ID NO: 577), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39689.1 (SEQ ID NO: 578), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39695.1 (SEQ ID NO: 579), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39701.1 (SEQ ID NO: 580), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39707.1 (SEQ ID NO: 581), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39713.1 (SEQ ID NO: 582), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39719.1 (SEQ ID NO: 583), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39725.1 (SEQ ID NO: 584),

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39684.1 (SEQ ID NO: 585), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39690.1 (SEQ ID NO: 586), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39696.1 (SEQ ID NO: 587), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39702.1 (SEQ ID NO: 588), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39708.1 (SEQ ID NO: 589), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39714.1 (SEQ ID NO: 590), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39720.1 (SEQ ID NO: 591), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39726.1 (SEQ ID NO: 592), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39685.1 (SEQ ID NO: 593), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39691.1 (SEQ ID NO: 594), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39697.1 (SEQ ID NO: 595), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39703.1 (SEQ ID NO: 596), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39709.1 (SEQ ID NO: 597), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39715.1 (SEQ ID NO: 598), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39721.1 (SEQ ID NO: 599), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39727.1 (SEQ ID NO: 600), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39686.1 (SEQ ID NO: 601), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39692.1 (SEQ ID NO: 602), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39698.1 (SEQ ID NO: 603), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39704.1 (SEQ ID NO: 604), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39710.1 (SEQ ID NO: 605), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39716.1 (SEQ ID NO: 606), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39722.1 (SEQ ID NO: 607), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39728.1 (SEQ ID NO: 608), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39687.1 (SEQ ID NO: 609), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39693.1 (SEQ ID NO: 610), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39699.1 (SEQ ID NO: 611), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39705.1 (SEQ ID NO: 612), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39711.1 (SEQ ID NO: 613), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39717.1 (SEQ ID NO: 614), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39723.1 (SEQ ID NO: 615), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39729.1 (SEQ ID NO: 616), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39688.1 (SEQ ID NO: 617), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39694.1 (SEQ ID NO: 618), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39700.1 (SEQ ID NO: 619), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39706.1 (SEQ ID NO: 620), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39712.1 (SEQ ID NO: 621), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39718.1 (SEQ ID NO: 622), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39724.1 (SEQ ID NO: 623), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39730.1 (SEQ ID NO: 624), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39736.1 (SEQ ID NO: 625),

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39742.1 (SEQ ID NO: 626), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39748.1 (SEQ ID NO: 627), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39754.1 (SEQ ID NO: 628), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39760.1 (SEQ ID NO: 629), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39766.1 (SEQ ID NO: 630), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39772.1 (SEQ ID NO: 631), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39731.1 (SEQ ID NO: 632), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39737.1 (SEQ ID NO: 633), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39743.1 (SEQ ID NO: 634), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39749.1 (SEQ ID NO: 635), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39755.1 (SEQ ID NO: 636), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39761.1 (SEQ ID NO: 637), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39767.1 (SEQ ID NO: 638), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39773.1 (SEQ ID NO: 639), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39732.1 (SEQ ID NO: 640), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39738.1 (SEQ ID NO: 641), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39744.1 (SEQ ID NO: 642), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39750.1 (SEQ ID NO: 643), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39756.1 (SEQ ID NO: 644), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39762.1 (SEQ ID NO: 645), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39768.1 (SEQ ID NO: 646), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39774.1 (SEQ ID NO: 647), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39733.1 (SEQ ID NO: 648), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39739.1 (SEQ ID NO: 649), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39745.1 (SEQ ID NO: 650), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39751.1 (SEQ ID NO: 651), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39757.1 (SEQ ID NO: 652), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39763.1 (SEQ ID NO: 653), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39769.1 (SEQ ID NO: 654), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39775.1 (SEQ ID NO: 655), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39734.1 (SEQ ID NO: 656), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39740.1 (SEQ ID NO: 657), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39746.1 (SEQ ID NO: 658), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39752.1 (SEQ ID NO: 659), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39758.1 (SEQ ID NO: 660), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39764.1 (SEQ ID NO: 661), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39770.1 (SEQ ID NO: 662), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39776.1 (SEQ ID NO: 663), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39735.1 (SEQ ID NO: 664), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39741.1 (SEQ ID NO: 665), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39747.1 (SEQ ID NO: 666),

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39753.1 (SEQ ID NO: 667), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39759.1 (SEQ ID NO: 668), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39765.1 (SEQ ID NO: 669), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39771.1 (SEQ ID NO: 670), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39778.1 (SEQ ID NO: 671), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39784.1 (SEQ ID NO: 672), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39790.1 (SEQ ID NO: 673), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39796.1 (SEQ ID NO: 674), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39802.1 (SEQ ID NO: 675), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39808.1 (SEQ ID NO: 676), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39814.1 (SEQ ID NO: 677), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39820.1 (SEQ ID NO: 678), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39779.1 (SEQ ID NO: 679), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39785.1 (SEQ ID NO: 680), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39791.1 (SEQ ID NO: 681), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39797.1 (SEQ ID NO: 682), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39803.1 (SEQ ID NO: 683), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39809.1 (SEQ ID NO: 684), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39815.1 (SEQ ID NO: 685), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39821.1 (SEQ ID NO: 686), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39780.1 (SEQ ID NO: 687), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39786.1 (SEQ ID NO: 688), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39792.1 (SEQ ID NO: 689), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39798.1 (SEQ ID NO: 690), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39804.1 (SEQ ID NO: 691), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39810.1 (SEQ ID NO: 692), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39816.1 (SEQ ID NO: 693), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39822.1 (SEQ ID NO: 694), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39781.1 (SEQ ID NO: 695), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39787.1 (SEQ ID NO: 696), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39793.1 (SEQ ID NO: 697), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39799.1 (SEQ ID NO: 698), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39805.1 (SEQ ID NO: 699), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39811.1 (SEQ ID NO: 700), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39817.1 (SEQ ID NO: 701), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39823.1 (SEQ ID NO: 702), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39782.1 (SEQ ID NO: 703), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39788.1 (SEQ ID NO: 704), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39794.1 (SEQ ID NO: 705), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39800.1 (SEQ ID NO: 706), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39806.1 (SEQ ID NO: 707),

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39812.1 (SEQ ID NO: 708), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39818.1 (SEQ ID NO: 709), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39824.1 (SEQ ID NO: 710), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39783.1 (SEQ ID NO: 711), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39789.1 (SEQ ID NO: 712), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39795.1 (SEQ ID NO: 713), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39801.1 (SEQ ID NO: 714), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39807.1 (SEQ ID NO: 715), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39813.1 (SEQ ID NO: 716), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39819.1 (SEQ ID NO: 717), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39825.1 (SEQ ID NO: 718), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39831.1 (SEQ ID NO: 719), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39837.1 (SEQ ID NO: 720), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39843.1 (SEQ ID NO: 721), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39849.1 (SEQ ID NO: 722), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39855.1 (SEQ ID NO: 723), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39861.1 (SEQ ID NO: 724), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39867.1 (SEQ ID NO: 725), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39826.1 (SEQ ID NO: 726), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39832.1 (SEQ ID NO: 727), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39838.1 (SEQ ID NO: 728), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39844.1 (SEQ ID NO: 729), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39850.1 (SEQ ID NO: 730), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39856.1 (SEQ ID NO: 731), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39862.1 (SEQ ID NO: 732), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39868.1 (SEQ ID NO: 733), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39827.1 (SEQ ID NO: 734), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39833.1 (SEQ ID NO: 735), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39839.1 (SEQ ID NO: 736), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39845.1 (SEQ ID NO: 737), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39851.1 (SEQ ID NO: 738), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39857.1 (SEQ ID NO: 739), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39863.1 (SEQ ID NO: 740), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39869.1 (SEQ ID NO: 741), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39828.1 (SEQ ID NO: 742), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39834.1 (SEQ ID NO: 743), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39840.1 (SEQ ID NO: 744), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39846.1 (SEQ ID NO: 745), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39852.1 (SEQ ID NO: 746), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39858.1 (SEQ ID NO: 747), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39864.1 (SEQ ID NO: 748),

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39870.1 (SEQ ID NO: 749), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39829.1 (SEQ ID NO: 750), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39835.1 (SEQ ID NO: 751), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39841.1 (SEQ ID NO: 752), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39853.1 (SEQ ID NO: 753), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39859.1 (SEQ ID NO: 754), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39865.1 (SEQ ID NO: 755), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39871.1 (SEQ ID NO: 756), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39830.1 (SEQ ID NO: 757), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39836.1 (SEQ ID NO: 758), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39842.1 (SEQ ID NO: 759), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39848.1 (SEQ ID NO: 760), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39854.1 (SEQ ID NO: 761), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39860.1 (SEQ ID NO: 762), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39866.1 (SEQ ID NO: 763), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39992.1 (SEQ ID NO: 764), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39998.1 (SEQ ID NO: 765), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40004.1 (SEQ ID NO: 766), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40010.1 (SEQ ID NO: 767), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40016.1 (SEQ ID NO: 768), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40022.1 (SEQ ID NO: 769), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40028.1 (SEQ ID NO: 770), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40034.1 (SEQ ID NO: 771), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39999.1 (SEQ ID NO: 772), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40005.1 (SEQ ID NO: 773), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40011.1 (SEQ ID NO: 774), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40017.1 (SEQ ID NO: 775), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40029.1 (SEQ ID NO: 776), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40035.1 (SEQ ID NO: 777), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39994.1 (SEQ ID NO: 778), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40000.1 (SEQ ID NO: 779), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40006.1 (SEQ ID NO: 780), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40012.1 (SEQ ID NO: 781), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40018.1 (SEQ ID NO: 782), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40024.1 (SEQ ID NO: 783), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40030.1 (SEQ ID NO: 784), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40036.1 (SEQ ID NO: 785), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39995.1 (SEQ ID NO: 786), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40001.1 (SEQ ID NO: 787), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40007.1 (SEQ ID NO: 788), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40013.1 (SEQ ID NO: 789),

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40019.1 (SEQ ID NO: 790), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40025.1 (SEQ ID NO: 791), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40031.1 (SEQ ID NO: 792), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40037.1 (SEQ ID NO: 793), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39996.1 (SEQ ID NO: 794), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40002.1 (SEQ ID NO: 795), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40008.1 (SEQ ID NO: 796), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40014.1 (SEQ ID NO: 797), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40020.1 (SEQ ID NO: 798), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40026.1 (SEQ ID NO: 799), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40032.1 (SEQ ID NO: 800), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40038.1 (SEQ ID NO: 801), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39997.1 (SEQ ID NO: 802), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40009.1 (SEQ ID NO: 803), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40015.1 (SEQ ID NO: 804), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40021.1 (SEQ ID NO: 805), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40027.1 (SEQ ID NO: 806), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40033.1 (SEQ ID NO: 807), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40039.1 (SEQ ID NO: 808), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40045.1 (SEQ ID NO: 809), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40051.1 (SEQ ID NO: 810), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40057.1 (SEQ ID NO: 811), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40063.1 (SEQ ID NO: 812), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40069.1 (SEQ ID NO: 813), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40075.1 (SEQ ID NO: 814), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40081.1 (SEQ ID NO: 815), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40040.1 (SEQ ID NO: 816), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40046.1 (SEQ ID NO: 817), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40052.1 (SEQ ID NO: 818), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40058.1 (SEQ ID NO: 819), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40064.1 (SEQ ID NO: 820), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40070.1 (SEQ ID NO: 821), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40076.1 (SEQ ID NO: 822), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40082.1 (SEQ ID NO: 823), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40041.1 (SEQ ID NO: 824), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40047.1 (SEQ ID NO: 825), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40053.1 (SEQ ID NO: 826), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40059.1 (SEQ ID NO: 827), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40065.1 (SEQ ID NO: 828), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40071.1 (SEQ ID NO: 829), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40077.1 (SEQ ID NO: 830),

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40083.1 (SEQ ID NO: 831), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40042.1 (SEQ ID NO: 832), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40048.1 (SEQ ID NO: 833), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40054.1 (SEQ ID NO: 834), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40060.1 (SEQ ID NO: 835), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40066.1 (SEQ ID NO: 836), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40072.1 (SEQ ID NO: 837), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40078.1 (SEQ ID NO: 838), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40084.1 (SEQ ID NO: 839), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40043.1 (SEQ ID NO: 840), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40049.1 (SEQ ID NO: 841), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40055.1 (SEQ ID NO: 842), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40061.1 (SEQ ID NO: 843), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40067.1 (SEQ ID NO: 844), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40073.1 (SEQ ID NO: 845), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40079.1 (SEQ ID NO: 846), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40085.1 (SEQ ID NO: 847), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40044.1 (SEQ ID NO: 848), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40050.1 (SEQ ID NO: 849), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40056.1 (SEQ ID NO: 850), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40062.1 (SEQ ID NO: 851), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40068.1 (SEQ ID NO: 852), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40074.1 (SEQ ID NO: 853), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40080.1 (SEQ ID NO: 854), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39720.1 (SEQ ID NOs: 1754), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39706.1 (SEQ ID NOs: 1755), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39712.1 (SEQ ID NOs: 1756), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39760.1 (SEQ ID NOs: 1757), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39732.1 (SEQ ID NOs: 1758), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35541.4 (SEQ ID NOs: 1759), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39735.1 or hs_KRAS_(—) 321_A22S26 (SEQ ID NOs: 1760), or amodified or unmodified variant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39741.1, or modified or unmodified variants thereof.

hs_KRAS_(—)322_A22S26 (SEQ ID NOs: 1761), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39778.1 (SEQ ID NOs: 1762), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39790.1 (SEQ ID NOs: 1763), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39822.1 (SEQ ID NOs: 1764), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35609.4 (SEQ ID NOs: 1765), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35581.4 (SEQ ID NOs: 1766), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39845.1 (SEQ ID NOs: 1767), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39858.1 (SEQ ID NOs: 1768), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39870.1 (SEQ ID NOs: 1769), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35576.4 (SEQ ID NOs: 1770), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35588.4 (SEQ ID NOs: 1771), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35600.1 (SEQ ID NOs: 1772), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-35606.1 (SEQ ID NOs: 1773), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38151.1 (SEQ ID NOs: 1774), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38163.1 (SEQ ID NOs: 1775), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-39999.1 (SEQ ID NOs: 1776), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38159.1 or hs_KRAS_(—) 528_A22S26 (SEQ ID NOs: 1777), or amodified or unmodified variant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38130.1 or hs_KRAS_(—) 531_A22S26 (SEQ ID NOs: 1778), or amodified or unmodified variant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38136.1 (SEQ ID NOs: 1779), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40036.1 (SEQ ID NOs: 1780), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40008.1 (SEQ ID NOs: 1781), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40021.1 (SEQ ID NOs: 1782), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40077.1 (SEQ ID NOs: 1783), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40072.1 (SEQ ID NOs: 1784), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40061.1 (SEQ ID NOs: 1785), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-40068.1 (SEQ ID NOs: 1786), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38131.1 (SEQ ID NOs: 1787), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: AD-38167.1 (SEQ ID NOs: 1788), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: hs_KRAS 1273_A22S26 (SEQ ID NOs: 1789), or a modified orunmodified variant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: hs_KRAS 2892_A37S26 (SEQ ID NOs: 1790), or a modified orunmodified variant thereof.

A RNAi agent comprising a first strand and a second strand, wherein thefirst strand comprises at least 15 contiguous nucleotides from a firststrand of: hs_KRAS 4731_A22S26 (SEQ ID NOs: 1791), or a modified orunmodified variant thereof.

Specific embodiments comprising a first strand of a RNAi agent disclosedherein

In one embodiment, the present disclosure pertains to a compositioncomprising any one or more of: a RNAi agent comprising a first and asecond strand, wherein the sequence of the first strand is the sequenceof a first strand of any RNAi agent from any of Tables 1 to 6, ormodified and unmodified variants thereof.

Thus, in various embodiments, the present disclosure pertains to acomposition comprising any one or more of the following:

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35523.3 (SEQ ID NO: 428), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35529.1 (SEQ ID NO: 429), or a modified or

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35535.4 (SEQ ID NO: 430), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35541.4 (SEQ ID NO: 431), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35547.4 (SEQ ID NO: 432), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35553.4 (SEQ ID NO: 433), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35559.4 (SEQ ID NO: 434), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35565.4 (SEQ ID NO: 435), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35524.4 (SEQ ID NO: 436), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35530.4 (SEQ ID NO: 437), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35536.4 (SEQ ID NO: 438), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35542.4 (SEQ ID NO: 439), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35548.4 (SEQ ID NO: 440), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35554.4 (SEQ ID NO: 441), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35560.2 (SEQ ID NO: 442), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35566.4 (SEQ ID NO: 443), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35525.2 (SEQ ID NO: 444), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35531.4 (SEQ ID NO: 445), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35537.4 (SEQ ID NO: 446), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35543.2 (SEQ ID NO: 447), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35549.4 (SEQ ID NO: 448), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35555.4 (SEQ ID NO: 449), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35561.4 (SEQ ID NO: 450), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35567.4 (SEQ ID NO: 451), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35526.4 (SEQ ID NO: 452), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35532.4 (SEQ ID NO: 453), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35538.4 (SEQ ID NO: 454), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35544.4 (SEQ ID NO: 455), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35550.4 (SEQ ID NO: 456), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35556.4 (SEQ ID NO: 457), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35562.4 (SEQ ID NO: 458), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35568.4 (SEQ ID NO: 459), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35527.4 (SEQ ID NO: 460), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35533.4 (SEQ ID NO: 461), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35539.4 (SEQ ID NO: 462), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35545.4 (SEQ ID NO: 463), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35551.4 (SEQ ID NO: 464), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35563.4 (SEQ ID NO: 465), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35528.4 (SEQ ID NO: 466), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35540.4 (SEQ ID NO: 467), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35546.4 (SEQ ID NO: 468), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35552.4 (SEQ ID NO: 469), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35558.4 (SEQ ID NO: 470), or a modified or

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35564.4 (SEQ ID NO: 471), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35570.4 (SEQ ID NO: 472), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35571.4 (SEQ ID NO: 473), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35577.4 (SEQ ID NO: 474), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35583.4 (SEQ ID NO: 475), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35589.4 (SEQ ID NO: 476), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35595.4 (SEQ ID NO: 477), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35601.4 (SEQ ID NO: 478), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35607.4 (SEQ ID NO: 479), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35613.4 (SEQ ID NO: 480), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35572.4 (SEQ ID NO: 481), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35578.4 (SEQ ID NO: 482), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35584.4 (SEQ ID NO: 483), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35590.4 (SEQ ID NO: 484), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35596.4 (SEQ ID NO: 485), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35602.4 (SEQ ID NO: 486), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35608.4 (SEQ ID NO: 487), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35614.4 (SEQ ID NO: 488), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35573.4 (SEQ ID NO: 489), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35579.4 (SEQ ID NO: 490), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35585.4 (SEQ ID NO: 491), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35591.4 (SEQ ID NO: 492), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35597.4 (SEQ ID NO: 493), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35603.4 (SEQ ID NO: 494), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35609.4 (SEQ ID NO: 495), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35615.4 (SEQ ID NO: 496), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35574.4 (SEQ ID NO: 497), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35580.1 (SEQ ID NO: 498), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35586.4 (SEQ ID NO: 499), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35592.4 (SEQ ID NO: 500), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35598.4 (SEQ ID NO: 501), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35604.4 (SEQ ID NO: 502), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35610.4 (SEQ ID NO: 503), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35616.4 (SEQ ID NO: 504), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35575.4 (SEQ ID NO: 505), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35581.4 (SEQ ID NO: 506), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35587.4 (SEQ ID NO: 507), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35593.4 (SEQ ID NO: 508), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35599.4 (SEQ ID NO: 509), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35605.4 (SEQ ID NO: 510), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35611.4 (SEQ ID NO: 511), or a modified or

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35617.4 (SEQ ID NO: 512), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35576.4 (SEQ ID NO: 513), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35588.4 (SEQ ID NO: 514), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35667.1 (SEQ ID NO: 515), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35673.1 (SEQ ID NO: 516), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35679.1 (SEQ ID NO: 517), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35685.1 (SEQ ID NO: 518), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35691.1 (SEQ ID NO: 519), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35557.1 (SEQ ID NO: 520), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35618.1 (SEQ ID NO: 521), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35569.1 (SEQ ID NO: 522), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35534.1 (SEQ ID NO: 523), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35582.1 (SEQ ID NO: 524), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35594.1 (SEQ ID NO: 525), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35600.1 (SEQ ID NO: 526), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35606.1 (SEQ ID NO: 527), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35612.1 (SEQ ID NO: 528), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38127.1 (SEQ ID NO: 529), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38133.1 (SEQ ID NO: 530), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38139.1 (SEQ ID NO: 531), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38145.1 (SEQ ID NO: 532), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38151.1 (SEQ ID NO: 533), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38157.1 (SEQ ID NO: 534), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38163.1 (SEQ ID NO: 535), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38169.1 (SEQ ID NO: 536), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38128.1 (SEQ ID NO: 537), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38134.1 (SEQ ID NO: 538), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38140.1 (SEQ ID NO: 539), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38146.1 (SEQ ID NO: 540), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38152.1 (SEQ ID NO: 541), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38158.1 (SEQ ID NO: 542), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38164.1 (SEQ ID NO: 543), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38170.1 (SEQ ID NO: 544), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38129.1 (SEQ ID NO: 545), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38135.1 (SEQ ID NO: 546), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38141.1 (SEQ ID NO: 547), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38147.1 (SEQ ID NO: 548), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38153.1 (SEQ ID NO: 549), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38159.1 (SEQ ID NO: 550), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38165.1 (SEQ ID NO: 551), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38171.1 (SEQ ID NO: 552), or a modified or

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38130.1 (SEQ ID NO: 553), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38136.1 (SEQ ID NO: 554), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38142.1 (SEQ ID NO: 555), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38148.1 (SEQ ID NO: 556), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38154.1 (SEQ ID NO: 557), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38160.1 (SEQ ID NO: 558), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38166.1 (SEQ ID NO: 559), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38172.1 (SEQ ID NO: 560), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38131.1 (SEQ ID NO: 561), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38137.1 (SEQ ID NO: 562), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38143.1 (SEQ ID NO: 563), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38149.1 (SEQ ID NO: 564), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38155.1 (SEQ ID NO: 565), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38161.1 (SEQ ID NO: 566), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38167.1 (SEQ ID NO: 567), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38173.1 (SEQ ID NO: 568), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38132.1 (SEQ ID NO: 569), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38138.1 (SEQ ID NO: 570), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38144.1 (SEQ ID NO: 571), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38150.1 (SEQ ID NO: 572), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38156.1 (SEQ ID NO: 573), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38162.1 (SEQ ID NO: 574), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38168.1 (SEQ ID NO: 575), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38174.1 (SEQ ID NO: 576), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39683.1 (SEQ ID NO: 577), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39689.1 (SEQ ID NO: 578), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39695.1 (SEQ ID NO: 579), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39701.1 (SEQ ID NO: 580), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39707.1 (SEQ ID NO: 581), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39713.1 (SEQ ID NO: 582), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39719.1 (SEQ ID NO: 583), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39725.1 (SEQ ID NO: 584), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39684.1 (SEQ ID NO: 585), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39690.1 (SEQ ID NO: 586), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39696.1 (SEQ ID NO: 587), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39702.1 (SEQ ID NO: 588), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39708.1 (SEQ ID NO: 589), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39714.1 (SEQ ID NO: 590), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39720.1 (SEQ ID NO: 591), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39726.1 (SEQ ID NO: 592), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39685.1 (SEQ ID NO: 593), or a modified or

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39691.1 (SEQ ID NO: 594), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39697.1 (SEQ ID NO: 595), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39703.1 (SEQ ID NO: 596), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39709.1 (SEQ ID NO: 597), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39715.1 (SEQ ID NO: 598), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39721.1 (SEQ ID NO: 599), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39727.1 (SEQ ID NO: 600), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39686.1 (SEQ ID NO: 601), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39692.1 (SEQ ID NO: 602), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39698.1 (SEQ ID NO: 603), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39704.1 (SEQ ID NO: 604), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39710.1 (SEQ ID NO: 605), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39716.1 (SEQ ID NO: 606), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39722.1 (SEQ ID NO: 607), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39728.1 (SEQ ID NO: 608), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39687.1 (SEQ ID NO: 609), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39693.1 (SEQ ID NO: 610), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39699.1 (SEQ ID NO: 611), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39705.1 (SEQ ID NO: 612), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39711.1 (SEQ ID NO: 613), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39717.1 (SEQ ID NO: 614), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39723.1 (SEQ ID NO: 615), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39729.1 (SEQ ID NO: 616), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39688.1 (SEQ ID NO: 617), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39694.1 (SEQ ID NO: 618), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39700.1 (SEQ ID NO: 619), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39706.1 (SEQ ID NO: 620), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39712.1 (SEQ ID NO: 621), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39718.1 (SEQ ID NO: 622), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39724.1 (SEQ ID NO: 623), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39730.1 (SEQ ID NO: 624), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39736.1 (SEQ ID NO: 625), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39742.1 (SEQ ID NO: 626), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39748.1 (SEQ ID NO: 627), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39754.1 (SEQ ID NO: 628), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39760.1 (SEQ ID NO: 629), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39766.1 (SEQ ID NO: 630), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39772.1 (SEQ ID NO: 631), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39731.1 (SEQ ID NO: 632), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39737.1 (SEQ ID NO: 633), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39743.1 (SEQ ID NO: 634), or a modified or

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39749.1 (SEQ ID NO: 635), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39755.1 (SEQ ID NO: 636), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39761.1 (SEQ ID NO: 637), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39767.1 (SEQ ID NO: 638), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39773.1 (SEQ ID NO: 639), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39732.1 (SEQ ID NO: 640), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39738.1 (SEQ ID NO: 641), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39744.1 (SEQ ID NO: 642), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39750.1 (SEQ ID NO: 643), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39756.1 (SEQ ID NO: 644), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39762.1 (SEQ ID NO: 645), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39768.1 (SEQ ID NO: 646), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39774.1 (SEQ ID NO: 647), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39733.1 (SEQ ID NO: 648), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39739.1 (SEQ ID NO: 649), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39745.1 (SEQ ID NO: 650), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39751.1 (SEQ ID NO: 651), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39757.1 (SEQ ID NO: 652), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39763.1 (SEQ ID NO: 653), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39769.1 (SEQ ID NO: 654), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39775.1 (SEQ ID NO: 655), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39734.1 (SEQ ID NO: 656), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39740.1 (SEQ ID NO: 657), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39746.1 (SEQ ID NO: 658), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39752.1 (SEQ ID NO: 659), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39758.1 (SEQ ID NO: 660), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39764.1 (SEQ ID NO: 661), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39770.1 (SEQ ID NO: 662), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39776.1 (SEQ ID NO: 663), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39735.1 (SEQ ID NO: 664), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39741.1 (SEQ ID NO: 665), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39747.1 (SEQ ID NO: 666), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39753.1 (SEQ ID NO: 667), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39759.1 (SEQ ID NO: 668), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39765.1 (SEQ ID NO: 669), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39771.1 (SEQ ID NO: 670), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39778.1 (SEQ ID NO: 671), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39784.1 (SEQ ID NO: 672), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39790.1 (SEQ ID NO: 673), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39796.1 (SEQ ID NO: 674), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39802.1 (SEQ ID NO: 675), or a modified or

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39808.1 (SEQ ID NO: 676), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39814.1 (SEQ ID NO: 677), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39820.1 (SEQ ID NO: 678), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39779.1 (SEQ ID NO: 679), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39785.1 (SEQ ID NO: 680), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39791.1 (SEQ ID NO: 681), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39797.1 (SEQ ID NO: 682), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39803.1 (SEQ ID NO: 683), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39809.1 (SEQ ID NO: 684), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39815.1 (SEQ ID NO: 685), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39821.1 (SEQ ID NO: 686), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39780.1 (SEQ ID NO: 687), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39786.1 (SEQ ID NO: 688), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39792.1 (SEQ ID NO: 689), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39798.1 (SEQ ID NO: 690), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39804.1 (SEQ ID NO: 691), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39810.1 (SEQ ID NO: 692), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39816.1 (SEQ ID NO: 693), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39822.1 (SEQ ID NO: 694), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39781.1 (SEQ ID NO: 695), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39787.1 (SEQ ID NO: 696), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39793.1 (SEQ ID NO: 697), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39799.1 (SEQ ID NO: 698), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39805.1 (SEQ ID NO: 699), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39811.1 (SEQ ID NO: 700), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39817.1 (SEQ ID NO: 701), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39823.1 (SEQ ID NO: 702), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39782.1 (SEQ ID NO: 703), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39788.1 (SEQ ID NO: 704), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39794.1 (SEQ ID NO: 705), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39800.1 (SEQ ID NO: 706), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39806.1 (SEQ ID NO: 707), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39812.1 (SEQ ID NO: 708), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39818.1 (SEQ ID NO: 709), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39824.1 (SEQ ID NO: 710), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39783.1 (SEQ ID NO: 711), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39789.1 (SEQ ID NO: 712), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39795.1 (SEQ ID NO: 713), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39801.1 (SEQ ID NO: 714), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39807.1 (SEQ ID NO: 715), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39813.1 (SEQ ID NO: 716), or a modified or

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39819.1 (SEQ ID NO: 717), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39825.1 (SEQ ID NO: 718), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39831.1 (SEQ ID NO: 719), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39837.1 (SEQ ID NO: 720), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39843.1 (SEQ ID NO: 721), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39849.1 (SEQ ID NO: 722), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39855.1 (SEQ ID NO: 723), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39861.1 (SEQ ID NO: 724), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39867.1 (SEQ ID NO: 725), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39826.1 (SEQ ID NO: 726), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39832.1 (SEQ ID NO: 727), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39838.1 (SEQ ID NO: 728), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39844.1 (SEQ ID NO: 729), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39850.1 (SEQ ID NO: 730), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39856.1 (SEQ ID NO: 731), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39862.1 (SEQ ID NO: 732), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39868.1 (SEQ ID NO: 733), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39827.1 (SEQ ID NO: 734), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39833.1 (SEQ ID NO: 735), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39839.1 (SEQ ID NO: 736), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39845.1 (SEQ ID NO: 737), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39851.1 (SEQ ID NO: 738), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39857.1 (SEQ ID NO: 739), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39863.1 (SEQ ID NO: 740), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39869.1 (SEQ ID NO: 741), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39828.1 (SEQ ID NO: 742), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39834.1 (SEQ ID NO: 743), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39840.1 (SEQ ID NO: 744), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39846.1 (SEQ ID NO: 745), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39852.1 (SEQ ID NO: 746), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39858.1 (SEQ ID NO: 747), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39864.1 (SEQ ID NO: 748), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39870.1 (SEQ ID NO: 749), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39829.1 (SEQ ID NO: 750), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39835.1 (SEQ ID NO: 751), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39841.1 (SEQ ID NO: 752), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39853.1 (SEQ ID NO: 753), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39859.1 (SEQ ID NO: 754), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39865.1 (SEQ ID NO: 755), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39871.1 (SEQ ID NO: 756), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39830.1 (SEQ ID NO: 757), or a modified or

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39836.1 (SEQ ID NO: 758), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39842.1 (SEQ ID NO: 759), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39848.1 (SEQ ID NO: 760), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39854.1 (SEQ ID NO: 761), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39860.1 (SEQ ID NO: 762), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39866.1 (SEQ ID NO: 763), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39992.1 (SEQ ID NO: 764), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39998.1 (SEQ ID NO: 765), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40004.1 (SEQ ID NO: 766), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40010.1 (SEQ ID NO: 767), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40016.1 (SEQ ID NO: 768), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40022.1 (SEQ ID NO: 769), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40028.1 (SEQ ID NO: 770), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40034.1 (SEQ ID NO: 771), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39999.1 (SEQ ID NO: 772), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40005.1 (SEQ ID NO: 773), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40011.1 (SEQ ID NO: 774), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40017.1 (SEQ ID NO: 775), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40029.1 (SEQ ID NO: 776), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40035.1 (SEQ ID NO: 777), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39994.1 (SEQ ID NO: 778), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40000.1 (SEQ ID NO: 779), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40006.1 (SEQ ID NO: 780), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40012.1 (SEQ ID NO: 781), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40018.1 (SEQ ID NO: 782), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40024.1 (SEQ ID NO: 783), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40030.1 (SEQ ID NO: 784), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40036.1 (SEQ ID NO: 785), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39995.1 (SEQ ID NO: 786), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40001.1 (SEQ ID NO: 787), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40007.1 (SEQ ID NO: 788), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40013.1 (SEQ ID NO: 789), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40019.1 (SEQ ID NO: 790), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40025.1 (SEQ ID NO: 791), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40031.1 (SEQ ID NO: 792), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40037.1 (SEQ ID NO: 793), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39996.1 (SEQ ID NO: 794), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40002.1 (SEQ ID NO: 795), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40008.1 (SEQ ID NO: 796), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40014.1 (SEQ ID NO: 797), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40020.1 (SEQ ID NO: 798), or a modified or

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40026.1 (SEQ ID NO: 799), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40032.1 (SEQ ID NO: 800), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40038.1 (SEQ ID NO: 801), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39997.1 (SEQ ID NO: 802), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40009.1 (SEQ ID NO: 803), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40015.1 (SEQ ID NO: 804), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40021.1 (SEQ ID NO: 805), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40027.1 (SEQ ID NO: 806), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40033.1 (SEQ ID NO: 807), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40039.1 (SEQ ID NO: 808), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40045.1 (SEQ ID NO: 809), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40051.1 (SEQ ID NO: 810), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40057.1 (SEQ ID NO: 811), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40063.1 (SEQ ID NO: 812), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40069.1 (SEQ ID NO: 813), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40075.1 (SEQ ID NO: 814), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40081.1 (SEQ ID NO: 815), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40040.1 (SEQ ID NO: 816), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40046.1 (SEQ ID NO: 817), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40052.1 (SEQ ID NO: 818), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40058.1 (SEQ ID NO: 819), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40064.1 (SEQ ID NO: 820), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40070.1 (SEQ ID NO: 821), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40076.1 (SEQ ID NO: 822), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40082.1 (SEQ ID NO: 823), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40041.1 (SEQ ID NO: 824), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40047.1 (SEQ ID NO: 825), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40053.1 (SEQ ID NO: 826), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40059.1 (SEQ ID NO: 827), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40065.1 (SEQ ID NO: 828), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40071.1 (SEQ ID NO: 829), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40077.1 (SEQ ID NO: 830), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40083.1 (SEQ ID NO: 831), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40042.1 (SEQ ID NO: 832), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40048.1 (SEQ ID NO: 833), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40054.1 (SEQ ID NO: 834), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40060.1 (SEQ ID NO: 835), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40066.1 (SEQ ID NO: 836), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40072.1 (SEQ ID NO: 837), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40078.1 (SEQ ID NO: 838), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40084.1 (SEQ ID NO: 839), or a modified or

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40043.1 (SEQ ID NO: 840), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40049.1 (SEQ ID NO: 841), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40055.1 (SEQ ID NO: 842), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40061.1 (SEQ ID NO: 843), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40067.1 (SEQ ID NO: 844), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40073.1 (SEQ ID NO: 845), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40079.1 (SEQ ID NO: 846), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40085.1 (SEQ ID NO: 847), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40044.1 (SEQ ID NO: 848), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40050.1 (SEQ ID NO: 849), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40056.1 (SEQ ID NO: 850), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40062.1 (SEQ ID NO: 851), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40068.1 (SEQ ID NO: 852), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40074.1 (SEQ ID NO: 853), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40080.1 (SEQ ID NO: 854), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39720.1 (SEQ ID NOs: 1716 and 1754), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39706.1 (SEQ ID NOs: 1717 and 1755), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39712.1 (SEQ ID NOs: 1718 and 1756), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39760.1 (SEQ ID NOs: 1719 and 1757), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39732.1 (SEQ ID NOs: 1720 and 1758), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35541.4 (SEQ ID NOs: 1721 and 1759), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39735.1 or hs_KRAS_(—)321_A22S26 (SEQ ID NOs: 1722 and 1760), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39741.1, or modified or unmodified variants thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:hs_KRAS_(—)322_A22S26 (SEQ ID NOs: 1723 and 1761), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39778.1 (SEQ ID NOs: 1724 and 1762), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39790.1 (SEQ ID NOs: 1725 and 1763), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39822.1 (SEQ ID NOs: 1726 and 1764), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35609.4 (SEQ ID NOs: 1727 and 1765), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35581.4 (SEQ ID NOs: 1728 and 1766), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39845.1 (SEQ ID NOs: 1729 and 1767), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39858.1 (SEQ ID NOs: 1730 and 1768), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39870.1 (SEQ ID NOs: 1731 and 1769), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35576.4 (SEQ ID NOs: 1732 and 1770), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35588.4 (SEQ ID NOs: 1733 and 1771), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35600.1 (SEQ ID NOs: 1734 and 1772), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-35606.1 (SEQ ID NOs: 1735 and 1773), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38151.1 (SEQ ID NOs: 1736 and 1774), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38163.1 (SEQ ID NOs: 1737 and 1775), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-39999.1 (SEQ ID NOs: 1738 and 1776), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38159.1 or hs_KRAS_(—)528_A22S26 (SEQ ID NOs: 1739 and 1777), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38130.1 or hs_KRAS_(—)531_A22S26 (SEQ ID NOs: 1740 and 1778), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38136.1 (SEQ ID NOs: 1741 and 1779), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40036.1 (SEQ ID NOs: 1742 and 1780), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40008.1 (SEQ ID NOs: 1743 and 1781), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40021.1 (SEQ ID NOs: 1744 and 1782), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40077.1 (SEQ ID NOs: 1745 and 1783), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40072.1 (SEQ ID NOs: 1746 and 1784), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40061.1 (SEQ ID NOs: 1747 and 1785), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-40068.1 (SEQ ID NOs: 1748 and 1786), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38131.1 (SEQ ID NOs: 1749 and 1787), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:AD-38167.1 (SEQ ID NOs: 1750 and 1788), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:hs_KRAS 1273_A22S26 (SEQ ID NOs: 1751 and 1789), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:hs_KRAS 2892_A37S26 (SEQ ID NOs: 1752 and 1790), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first strand is the sequence of a first strand of:hs_KRAS 4731_A22S26 (SEQ ID NOs: 1753 and 1791), or a modified orunmodified variant thereof.

Specific embodiments comprising the first and/or second strands of aRNAi agent disclosed herein

In one embodiment, the present disclosure pertains to a compositioncomprising any one or more of: a RNAi agent comprising a first and asecond strand, wherein the sequences of the first and/or second strandscomprise the sequences of a first and/or second strand of any RNAi agentfrom any of Tables 1 to 6, or modified and unmodified variants thereof.

Thus, in various embodiments, the present disclosure pertains to acomposition comprising any one or more of the following:

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35523.3 (SEQ ID NOs: 1 and 428), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35529.1 (SEQ ID NOs: 2 and 429), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35535.4 (SEQ ID NOs: 3 and 430), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35541.4 (SEQ ID NOs: 4 and 431), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35547.4 (SEQ ID NOs: 5 and 432), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35553.4 (SEQ ID NOs: 6 and 433), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35559.4 (SEQ ID NOs: 7 and 434), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35565.4 (SEQ ID NOs: 8 and 435), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35524.4 (SEQ ID NOs: 9 and 436), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35530.4 (SEQ ID NOs: 10 and 437), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35536.4 (SEQ ID NOs: 11 and 438), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35542.4 (SEQ ID NOs: 12 and 439), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35548.4 (SEQ ID NOs: 13 and 440), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35554.4 (SEQ ID NOs: 14 and 441), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35560.2 (SEQ ID NOs: 15 and 442), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35566.4 (SEQ ID NOs: 16 and 443), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35525.2 (SEQ ID NOs: 17 and 444), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35531.4 (SEQ ID NOs: 18 and 445), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35537.4 (SEQ ID NOs: 19 and 446), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35543.2 (SEQ ID NOs: 20 and 447), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35549.4 (SEQ ID NOs: 21 and 448), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35555.4 (SEQ ID NOs: 22 and 449), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35561.4 (SEQ ID NOs: 23 and 450), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35567.4 (SEQ ID NOs: 24 and 451), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35526.4 (SEQ ID NOs: 25 and 452), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35532.4 (SEQ ID NOs: 26 and 453), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35538.4 (SEQ ID NOs: 27 and 454), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35544.4 (SEQ ID NOs: 28 and 455), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35550.4 (SEQ ID NOs: 29 and 456), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35556.4 (SEQ ID NOs: 30 and 457), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35562.4 (SEQ ID NOs: 31 and 458), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35568.4 (SEQ ID NOs: 32 and 459), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35527.4 (SEQ ID NOs: 33 and 460), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35533.4 (SEQ ID NOs: 34 and 461), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35539.4 (SEQ ID NOs: 35 and 462), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35545.4 (SEQ ID NOs: 36 and 463), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35551.4 (SEQ ID NOs: 37 and 464), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35563.4 (SEQ ID NOs: 38 and 465), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35528.4 (SEQ ID NOs: 39 and 466), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35540.4 (SEQ ID NOs: 40 and 467), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35546.4 (SEQ ID NOs: 41 and 468), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35552.4 (SEQ ID NOs: 42 and 469), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35558.4 (SEQ ID NOs: 43 and 470), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35564.4 (SEQ ID NOs: 44 and 471), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35570.4 (SEQ ID NOs: 45 and 472), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35571.4 (SEQ ID NOs: 46 and 473), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35577.4 (SEQ ID NOs: 47 and 474), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35583.4 (SEQ ID NOs: 48 and 475), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35589.4 (SEQ ID NOs: 49 and 476), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35595.4 (SEQ ID NOs: 50 and 477), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35601.4 (SEQ ID NOs: 51 and 478), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35607.4 (SEQ ID NOs: 52 and 479), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35613.4 (SEQ ID NOs: 53 and 480), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35572.4 (SEQ ID NOs: 54 and 481), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35578.4 (SEQ ID NOs: 55 and 482), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35584.4 (SEQ ID NOs: 56 and 483), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35590.4 (SEQ ID NOs: 57 and 484), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35596.4 (SEQ ID NOs: 58 and 485), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35602.4 (SEQ ID NOs: 59 and 486), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35608.4 (SEQ ID NOs: 60 and 487), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35614.4 (SEQ ID NOs: 61 and 488), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35573.4 (SEQ ID NOs: 62 and 489), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35579.4 (SEQ ID NOs: 63 and 490), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35585.4 (SEQ ID NOs: 64 and 491), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35591.4 (SEQ ID NOs: 65 and 492), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35597.4 (SEQ ID NOs: 66 and 493), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35603.4 (SEQ ID NOs: 67 and 494), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35609.4 (SEQ ID NOs: 68 and 495), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35615.4 (SEQ ID NOs: 69 and 496), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35574.4 (SEQ ID NOs: 70 and 497), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35580.1 (SEQ ID NOs: 71 and 498), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35586.4 (SEQ ID NOs: 72 and 499), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35592.4 (SEQ ID NOs: 73 and 500), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35598.4 (SEQ ID NOs: 74 and 501), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35604.4 (SEQ ID NOs: 75 and 502), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35610.4 (SEQ ID NOs: 76 and 503), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35616.4 (SEQ ID NOs: 77 and 504), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35575.4 (SEQ ID NOs: 78 and 505), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35581.4 (SEQ ID NOs: 79 and 506), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35587.4 (SEQ ID NOs: 80 and 507), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35593.4 (SEQ ID NOs: 81 and 508), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35599.4 (SEQ ID NOs: 82 and 509), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35605.4 (SEQ ID NOs: 83 and 510), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35611.4 (SEQ ID NOs: 84 and 511), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35617.4 (SEQ ID NOs: 85 and 512), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35576.4 (SEQ ID NOs: 86 and 513), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35588.4 (SEQ ID NOs: 87 and 514), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35667.1 (SEQ ID NOs: 88 and 515), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35673.1 (SEQ ID NOs: 89 and 516), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35679.1 (SEQ ID NOs: 90 and 517), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35685.1 (SEQ ID NOs: 91 and 518), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35691.1 (SEQ ID NOs: 92 and 519), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35557.1 (SEQ ID NOs: 93 and 520), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35618.1 (SEQ ID NOs: 94 and 521), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35569.1 (SEQ ID NOs: 95 and 522), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35534.1 (SEQ ID NOs: 96 and 523), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35582.1 (SEQ ID NOs: 97 and 524), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35594.1 (SEQ ID NOs: 98 and 525), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35600.1 (SEQ ID NOs: 99 and 526), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35606.1 (SEQ ID NOs: 100 and 527), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35612.1 (SEQ ID NOs: 101 and 528), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38127.1 (SEQ ID NOs: 102 and 529), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38133.1 (SEQ ID NOs: 103 and 530), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38139.1 (SEQ ID NOs: 104 and 531), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38145.1 (SEQ ID NOs: 105 and 532), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38151.1 (SEQ ID NOs: 106 and 533), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38157.1 (SEQ ID NOs: 107 and 534), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38163.1 (SEQ ID NOs: 108 and 535), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38169.1 (SEQ ID NOs: 109 and 536), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38128.1 (SEQ ID NOs: 110 and 537), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38134.1 (SEQ ID NOs: 111 and 538), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38140.1 (SEQ ID NOs: 112 and 539), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38146.1 (SEQ ID NOs: 113 and 540), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38152.1 (SEQ ID NOs: 114 and 541), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38158.1 (SEQ ID NOs: 115 and 542), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38164.1 (SEQ ID NOs: 116 and 543), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38170.1 (SEQ ID NOs: 117 and 544), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38129.1 (SEQ ID NOs: 118 and 545), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38135.1 (SEQ ID NOs: 119 and 546), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38141.1 (SEQ ID NOs: 120 and 547), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38147.1 (SEQ ID NOs: 121 and 548), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38153.1 (SEQ ID NOs: 122 and 549), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38159.1 (SEQ ID NOs: 123 and 550), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38165.1 (SEQ ID NOs: 124 and 551), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38171.1 (SEQ ID NOs: 125 and 552), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38130.1 (SEQ ID NOs: 126 and 553), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38136.1 (SEQ ID NOs: 127 and 554), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38142.1 (SEQ ID NOs: 128 and 555), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38148.1 (SEQ ID NOs: 129 and 556), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38154.1 (SEQ ID NOs: 130 and 557), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38160.1 (SEQ ID NOs: 131 and 558), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38166.1 (SEQ ID NOs: 132 and 559), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38172.1 (SEQ ID NOs: 133 and 560), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38131.1 (SEQ ID NOs: 134 and 561), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38137.1 (SEQ ID NOs: 135 and 562), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38143.1 (SEQ ID NOs: 136 and 563), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38149.1 (SEQ ID NOs: 137 and 564), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38155.1 (SEQ ID NOs: 138 and 565), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38161.1 (SEQ ID NOs: 139 and 566), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38167.1 (SEQ ID NOs: 140 and 567), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38173.1 (SEQ ID NOs: 141 and 568), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38132.1 (SEQ ID NOs: 142 and 569), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38138.1 (SEQ ID NOs: 143 and 570), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38144.1 (SEQ ID NOs: 144 and 571), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38150.1 (SEQ ID NOs: 145 and 572), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38156.1 (SEQ ID NOs: 146 and 573), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38162.1 (SEQ ID NOs: 147 and 574), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38168.1 (SEQ ID NOs: 148 and 575), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38174.1 (SEQ ID NOs: 149 and 576), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39683.1 (SEQ ID NOs: 150 and 577), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39689.1 (SEQ ID NOs: 151 and 578), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39695.1 (SEQ ID NOs: 152 and 579), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39701.1 (SEQ ID NOs: 153 and 580), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39707.1 (SEQ ID NOs: 154 and 581), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39713.1 (SEQ ID NOs: 155 and 582), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39719.1 (SEQ ID NOs: 156 and 583), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39725.1 (SEQ ID NOs: 157 and 584), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39684.1 (SEQ ID NOs: 158 and 585), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39690.1 (SEQ ID NOs: 159 and 586), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39696.1 (SEQ ID NOs: 160 and 587), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39702.1 (SEQ ID NOs: 161 and 588), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39708.1 (SEQ ID NOs: 162 and 589), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39714.1 (SEQ ID NOs: 163 and 590), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39720.1 (SEQ ID NOs: 164 and 591), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39726.1 (SEQ ID NOs: 165 and 592), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39685.1 (SEQ ID NOs: 166 and 593), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39691.1 (SEQ ID NOs: 167 and 594), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39697.1 (SEQ ID NOs: 168 and 595), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39703.1 (SEQ ID NOs: 169 and 596), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39709.1 (SEQ ID NOs: 170 and 597), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39715.1 (SEQ ID NOs: 171 and 598), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39721.1 (SEQ ID NOs: 172 and 599), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39727.1 (SEQ ID NOs: 173 and 600), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39686.1 (SEQ ID NOs: 174 and 601), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39692.1 (SEQ ID NOs: 175 and 602), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39698.1 (SEQ ID NOs: 176 and 603), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39704.1 (SEQ ID NOs: 177 and 604), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39710.1 (SEQ ID NOs: 178 and 605), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39716.1 (SEQ ID NOs: 179 and 606), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39722.1 (SEQ ID NOs: 180 and 607), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39728.1 (SEQ ID NOs: 181 and 608), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39687.1 (SEQ ID NOs: 182 and 609), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39693.1 (SEQ ID NOs: 183 and 610), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39699.1 (SEQ ID NOs: 184 and 611), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39705.1 (SEQ ID NOs: 185 and 612), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39711.1 (SEQ ID NOs: 186 and 613), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39717.1 (SEQ ID NOs: 187 and 614), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39723.1 (SEQ ID NOs: 188 and 615), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39729.1 (SEQ ID NOs: 189 and 616), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39688.1 (SEQ ID NOs: 190 and 617), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39694.1 (SEQ ID NOs: 191 and 618), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39700.1 (SEQ ID NOs: 192 and 619), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39706.1 (SEQ ID NOs: 193 and 620), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39712.1 (SEQ ID NOs: 194 and 621), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39718.1 (SEQ ID NOs: 195 and 622), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39724.1 (SEQ ID NOs: 196 and 623), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39730.1 (SEQ ID NOs: 197 and 624), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39736.1 (SEQ ID NOs: 198 and 625), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39742.1 (SEQ ID NOs: 199 and 626), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39748.1 (SEQ ID NOs: 200 and 627), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39754.1 (SEQ ID NOs: 201 and 628), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39760.1 (SEQ ID NOs: 202 and 629), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39766.1 (SEQ ID NOs: 203 and 630), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39772.1 (SEQ ID NOs: 204 and 631), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39731.1 (SEQ ID NOs: 205 and 632), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39737.1 (SEQ ID NOs: 206 and 633), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39743.1 (SEQ ID NOs: 207 and 634), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39749.1 (SEQ ID NOs: 208 and 635), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39755.1 (SEQ ID NOs: 209 and 636), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39761.1 (SEQ ID NOs: 210 and 637), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39767.1 (SEQ ID NOs: 211 and 638), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39773.1 (SEQ ID NOs: 212 and 639), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39732.1 (SEQ ID NOs: 213 and 640), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39738.1 (SEQ ID NOs: 214 and 641), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39744.1 (SEQ ID NOs: 215 and 642), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39750.1 (SEQ ID NOs: 216 and 643), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39756.1 (SEQ ID NOs: 217 and 644), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39762.1 (SEQ ID NOs: 218 and 645), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39768.1 (SEQ ID NOs: 219 and 646), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39774.1 (SEQ ID NOs: 220 and 647), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39733.1 (SEQ ID NOs: 221 and 648), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39739.1 (SEQ ID NOs: 222 and 649), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39745.1 (SEQ ID NOs: 223 and 650), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39751.1 (SEQ ID NOs: 224 and 651), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39757.1 (SEQ ID NOs: 225 and 652), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39763.1 (SEQ ID NOs: 226 and 653), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39769.1 (SEQ ID NOs: 227 and 654), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39775.1 (SEQ ID NOs: 228 and 655), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39734.1 (SEQ ID NOs: 229 and 656), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39740.1 (SEQ ID NOs: 230 and 657), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39746.1 (SEQ ID NOs: 231 and 658), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39752.1 (SEQ ID NOs: 232 and 659), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39758.1 (SEQ ID NOs: 233 and 660), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39764.1 (SEQ ID NOs: 234 and 661), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39770.1 (SEQ ID NOs: 235 and 662), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39776.1 (SEQ ID NOs: 236 and 663), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39735.1 (SEQ ID NOs: 237 and 664), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39741.1 (SEQ ID NOs: 238 and 665), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39747.1 (SEQ ID NOs: 239 and 666), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39753.1 (SEQ ID NOs: 240 and 667), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39759.1 (SEQ ID NOs: 241 and 668), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39765.1 (SEQ ID NOs: 242 and 669), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39771.1 (SEQ ID NOs: 243 and 670), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39778.1 (SEQ ID NOs: 244 and 671), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39784.1 (SEQ ID NOs: 245 and 672), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39790.1 (SEQ ID NOs: 246 and 673), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39796.1 (SEQ ID NOs: 247 and 674), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39802.1 (SEQ ID NOs: 248 and 675), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39808.1 (SEQ ID NOs: 249 and 676), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39814.1 (SEQ ID NOs: 250 and 677), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39820.1 (SEQ ID NOs: 251 and 678), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39779.1 (SEQ ID NOs: 252 and 679), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39785.1 (SEQ ID NOs: 253 and 680), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39791.1 (SEQ ID NOs: 254 and 681), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39797.1 (SEQ ID NOs: 255 and 682), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39803.1 (SEQ ID NOs: 256 and 683), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39809.1 (SEQ ID NOs: 257 and 684), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39815.1 (SEQ ID NOs: 258 and 685), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39821.1 (SEQ ID NOs: 259 and 686), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39780.1 (SEQ ID NOs: 260 and 687), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39786.1 (SEQ ID NOs: 261 and 688), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39792.1 (SEQ ID NOs: 262 and 689), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39798.1 (SEQ ID NOs: 263 and 690), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39804.1 (SEQ ID NOs: 264 and 691), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39810.1 (SEQ ID NOs: 265 and 692), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39816.1 (SEQ ID NOs: 266 and 693), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39822.1 (SEQ ID NOs: 267 and 694), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39781.1 (SEQ ID NOs: 268 and 695), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39787.1 (SEQ ID NOs: 269 and 696), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39793.1 (SEQ ID NOs: 270 and 697), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39799.1 (SEQ ID NOs: 271 and 698), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39805.1 (SEQ ID NOs: 272 and 699), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39811.1 (SEQ ID NOs: 273 and 700), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39817.1 (SEQ ID NOs: 274 and 701), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39823.1 (SEQ ID NOs: 275 and 702), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39782.1 (SEQ ID NOs: 276 and 703), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39788.1 (SEQ ID NOs: 277 and 704), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39794.1 (SEQ ID NOs: 278 and 705), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39800.1 (SEQ ID NOs: 279 and 706), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39806.1 (SEQ ID NOs: 280 and 707), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39812.1 (SEQ ID NOs: 281 and 708), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39818.1 (SEQ ID NOs: 282 and 709), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39824.1 (SEQ ID NOs: 283 and 710), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39783.1 (SEQ ID NOs: 284 and 711), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39789.1 (SEQ ID NOs: 285 and 712), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39795.1 (SEQ ID NOs: 286 and 713), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39801.1 (SEQ ID NOs: 287 and 714), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39807.1 (SEQ ID NOs: 288 and 715), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39813.1 (SEQ ID NOs: 289 and 716), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39819.1 (SEQ ID NOs: 290 and 717), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39825.1 (SEQ ID NOs: 291 and 718), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39831.1 (SEQ ID NOs: 292 and 719), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39837.1 (SEQ ID NOs: 293 and 720), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39843.1 (SEQ ID NOs: 294 and 721), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39849.1 (SEQ ID NOs: 295 and 722), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39855.1 (SEQ ID NOs: 296 and 723), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39861.1 (SEQ ID NOs: 297 and 724), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39867.1 (SEQ ID NOs: 298 and 725), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39826.1 (SEQ ID NOs: 299 and 726), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39832.1 (SEQ ID NOs: 300 and 727), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39838.1 (SEQ ID NOs: 301 and 728), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39844.1 (SEQ ID NOs: 302 and 729), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39850.1 (SEQ ID NOs: 303 and 730), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39856.1 (SEQ ID NOs: 304 and 731), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39862.1 (SEQ ID NOs: 305 and 732), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39868.1 (SEQ ID NOs: 306 and 733), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39827.1 (SEQ ID NOs: 307 and 734), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39833.1 (SEQ ID NOs: 308 and 735), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39839.1 (SEQ ID NOs: 309 and 736), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39845.1 (SEQ ID NOs: 310 and 737), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39851.1 (SEQ ID NOs: 311 and 738), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39857.1 (SEQ ID NOs: 312 and 739), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39863.1 (SEQ ID NOs: 313 and 740), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39869.1 (SEQ ID NOs: 314 and 741), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39828.1 (SEQ ID NOs: 315 and 742), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39834.1 (SEQ ID NOs: 316 and 743), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39840.1 (SEQ ID NOs: 317 and 744), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39846.1 (SEQ ID NOs: 318 and 745), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39852.1 (SEQ ID NOs: 319 and 746), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39858.1 (SEQ ID NOs: 320 and 747), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39864.1 (SEQ ID NOs: 321 and 748), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39870.1 (SEQ ID NOs: 322 and 749), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39829.1 (SEQ ID NOs: 323 and 750), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39835.1 (SEQ ID NOs: 324 and 751), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39841.1 (SEQ ID NOs: 325 and 752), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39853.1 (SEQ ID NOs: 326 and 753), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39859.1 (SEQ ID NOs: 327 and 754), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39865.1 (SEQ ID NOs: 328 and 755), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39871.1 (SEQ ID NOs: 329 and 756), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39830.1 (SEQ ID NOs: 330 and 757), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39836.1 (SEQ ID NOs: 331 and 758), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39842.1 (SEQ ID NOs: 332 and 759), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39848.1 (SEQ ID NOs: 333 and 760), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39854.1 (SEQ ID NOs: 334 and 761), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39860.1 (SEQ ID NOs: 335 and 762), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39866.1 (SEQ ID NOs: 336 and 763), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39992.1 (SEQ ID NOs: 337 and 764), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39998.1 (SEQ ID NOs: 338 and 765), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40004.1 (SEQ ID NOs: 339 and 766), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40010.1 (SEQ ID NOs: 340 and 767), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40016.1 (SEQ ID NOs: 341 and 768), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40022.1 (SEQ ID NOs: 342 and 769), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40028.1 (SEQ ID NOs: 343 and 770), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40034.1 (SEQ ID NOs: 344 and 771), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39999.1 (SEQ ID NOs: 345 and 772), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40005.1 (SEQ ID NOs: 346 and 773), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40011.1 (SEQ ID NOs: 347 and 774), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40017.1 (SEQ ID NOs: 348 and 775), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40029.1 (SEQ ID NOs: 349 and 776), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40035.1 (SEQ ID NOs: 350 and 777), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39994.1 (SEQ ID NOs: 351 and 778), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40000.1 (SEQ ID NOs: 352 and 779), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40006.1 (SEQ ID NOs: 353 and 780), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40012.1 (SEQ ID NOs: 354 and 781), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40018.1 (SEQ ID NOs: 355 and 782), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40024.1 (SEQ ID NOs: 356 and 783), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40030.1 (SEQ ID NOs: 357 and 784), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40036.1 (SEQ ID NOs: 358 and 785), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39995.1 (SEQ ID NOs: 359 and 786), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40001.1 (SEQ ID NOs: 360 and 787), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40007.1 (SEQ ID NOs: 361 and 788), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40013.1 (SEQ ID NOs: 362 and 789), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40019.1 (SEQ ID NOs: 363 and 790), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40025.1 (SEQ ID NOs: 364 and 791), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40031.1 (SEQ ID NOs: 365 and 792), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40037.1 (SEQ ID NOs: 366 and 793), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39996.1 (SEQ ID NOs: 367 and 794), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40002.1 (SEQ ID NOs: 368 and 795), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40008.1 (SEQ ID NOs: 369 and 796), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40014.1 (SEQ ID NOs: 370 and 797), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40020.1 (SEQ ID NOs: 371 and 798), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40026.1 (SEQ ID NOs: 372 and 799), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40032.1 (SEQ ID NOs: 373 and 800), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40038.1 (SEQ ID NOs: 374 and 801), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39997.1 (SEQ ID NOs: 375 and 802), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40009.1 (SEQ ID NOs: 376 and 803), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40015.1 (SEQ ID NOs: 377 and 804), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40021.1 (SEQ ID NOs: 378 and 805), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40027.1 (SEQ ID NOs: 379 and 806), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40033.1 (SEQ ID NOs: 380 and 807), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40039.1 (SEQ ID NOs: 381 and 808), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40045.1 (SEQ ID NOs: 382 and 809), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40051.1 (SEQ ID NOs: 383 and 810), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40057.1 (SEQ ID NOs: 384 and 811), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40063.1 (SEQ ID NOs: 385 and 812), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40069.1 (SEQ ID NOs: 386 and 813), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40075.1 (SEQ ID NOs: 387 and 814), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40081.1 (SEQ ID NOs: 388 and 815), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40040.1 (SEQ ID NOs: 389 and 816), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40046.1 (SEQ ID NOs: 390 and 817), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40052.1 (SEQ ID NOs: 391 and 818), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40058.1 (SEQ ID NOs: 392 and 819), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40064.1 (SEQ ID NOs: 393 and 820), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40070.1 (SEQ ID NOs: 394 and 821), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40076.1 (SEQ ID NOs: 395 and 822), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40082.1 (SEQ ID NOs: 396 and 823), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40041.1 (SEQ ID NOs: 397 and 824), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40047.1 (SEQ ID NOs: 398 and 825), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40053.1 (SEQ ID NOs: 399 and 826), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40059.1 (SEQ ID NOs: 400 and 827), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40065.1 (SEQ ID NOs: 401 and 828), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40071.1 (SEQ ID NOs: 402 and 829), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40077.1 (SEQ ID NOs: 403 and 830), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40083.1 (SEQ ID NOs: 404 and 831), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40042.1 (SEQ ID NOs: 405 and 832), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40048.1 (SEQ ID NOs: 406 and 833), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40054.1 (SEQ ID NOs: 407 and 834), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40060.1 (SEQ ID NOs: 408 and 835), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40066.1 (SEQ ID NOs: 409 and 836), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40072.1 (SEQ ID NOs: 410 and 837), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40078.1 (SEQ ID NOs: 411 and 838), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40084.1 (SEQ ID NOs: 412 and 839), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40043.1 (SEQ ID NOs: 413 and 840), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40049.1 (SEQ ID NOs: 414 and 841), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40055.1 (SEQ ID NOs: 415 and 842), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40061.1 (SEQ ID NOs: 416 and 843), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40067.1 (SEQ ID NOs: 417 and 844), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40073.1 (SEQ ID NOs: 418 and 845), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40079.1 (SEQ ID NOs: 419 and 846), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40085.1 (SEQ ID NOs: 420 and 847), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40044.1 (SEQ ID NOs: 421 and 848), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40050.1 (SEQ ID NOs: 422 and 849), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40056.1 (SEQ ID NOs: 423 and 850), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40062.1 (SEQ ID NOs: 424 and 851), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40068.1 (SEQ ID NOs: 425 and 852), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40074.1 (SEQ ID NOs: 426 and 853), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40080.1 (SEQ ID NOs: 427 and 854), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39720.1 (SEQ ID NOs: 1716 and 1754),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39706.1 (SEQ ID NOs: 1717 and 1755),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39712.1 (SEQ ID NOs: 1718 and 1756),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39760.1 (SEQ ID NOs: 1719 and 1757),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39732.1 (SEQ ID NOs: 1720 and 1758),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35541.4 (SEQ ID NOs: 1721 and 1759),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39735.1 or hs_KRAS_(—)321_A22S26 (SEQID NOs: 1722 and 1760), or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39741.1, or modified or unmodifiedvariants thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: hs_KRAS_(—) 322_A22S26 (SEQ ID NOs: 1723and 1761), or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39778.1 (SEQ ID NOs: 1724 and 1762),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39790.1 (SEQ ID NOs: 1725 and 1763),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39822.1 (SEQ ID NOs: 1726 and 1764),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35609.4 (SEQ ID NOs: 1727 and 1765),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35581.4 (SEQ ID NOs: 1728 and 1766),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39845.1 (SEQ ID NOs: 1729 and 1767),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39858.1 (SEQ ID NOs: 1730 and 1768),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39870.1 (SEQ ID NOs: 1731 and 1769),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35576.4 (SEQ ID NOs: 1732 and 1770),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35588.4 (SEQ ID NOs: 1733 and 1771),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35600.1 (SEQ ID NOs: 1734 and 1772),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-35606.1 (SEQ ID NOs: 1735 and 1773),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38151.1 (SEQ ID NOs: 1736 and 1774),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38163.1 (SEQ ID NOs: 1737 and 1775),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-39999.1 (SEQ ID NOs: 1738 and 1776),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38159.1 or hs_KRAS_(—)528_A22S26 (SEQID NOs: 1739 and 1777), or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38130.1 or hs_KRAS_(—)531_A22S26 (SEQID NOs: 1740 and 1778), or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38136.1 (SEQ ID NOs: 1741 and 1779),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40036.1 (SEQ ID NOs: 1742 and 1780),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40008.1 (SEQ ID NOs: 1743 and 1781),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40021.1 (SEQ ID NOs: 1744 and 1782),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40077.1 (SEQ ID NOs: 1745 and 1783),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40072.1 (SEQ ID NOs: 1746 and 1784),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40061.1 (SEQ ID NOs: 1747 and 1785),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-40068.1 (SEQ ID NOs: 1748 and 1786),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38131.1 (SEQ ID NOs: 1749 and 1787),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: AD-38167.1 (SEQ ID NOs: 1750 and 1788),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: hs_KRAS 1273_A22S26 (SEQ ID NOs: 1751 and1789), or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: hs_KRAS 2892_A37S26 (SEQ ID NOs: 1752 and1790), or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands comprise the sequences of afirst and/or second strand of: hs_KRAS 4731_A22S26 (SEQ ID NOs: 1753 and1791), or a modified or unmodified variant thereof.

Specific embodiments wherein the sequences of the first and/or secondstrands are the sequences of the first and/or second strands of a RNAiagent disclosed herein

In one embodiment, the present disclosure pertains to a compositioncomprising any one or more of: a RNAi agent comprising a first and asecond strand, wherein the sequences of the first and/or second strandsare the sequences of the first and/or second strands of any RNAi agentfrom any of Tables 1 to 6, or modified and unmodified variants thereof.

Thus, in various embodiments, the present disclosure pertains to acomposition comprising any one or more of the following:

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35523.3 (SEQ ID NOs: 1 and 428), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35529.1 (SEQ ID NOs: 2 and 429), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35535.4 (SEQ ID NOs: 3 and 430), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35541.4 (SEQ ID NOs: 4 and 431), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35547.4 (SEQ ID NOs: 5 and 432), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35553.4 (SEQ ID NOs: 6 and 433), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35559.4 (SEQ ID NOs: 7 and 434), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35565.4 (SEQ ID NOs: 8 and 435), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35524.4 (SEQ ID NOs: 9 and 436), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35530.4 (SEQ ID NOs: 10 and 437), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35536.4 (SEQ ID NOs: 11 and 438), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35542.4 (SEQ ID NOs: 12 and 439), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35548.4 (SEQ ID NOs: 13 and 440), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35554.4 (SEQ ID NOs: 14 and 441), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35560.2 (SEQ ID NOs: 15 and 442), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35566.4 (SEQ ID NOs: 16 and 443), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35525.2 (SEQ ID NOs: 17 and 444), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35531.4 (SEQ ID NOs: 18 and 445), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35537.4 (SEQ ID NOs: 19 and 446), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35543.2 (SEQ ID NOs: 20 and 447), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35549.4 (SEQ ID NOs: 21 and 448), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35555.4 (SEQ ID NOs: 22 and 449), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35561.4 (SEQ ID NOs: 23 and 450), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35567.4 (SEQ ID NOs: 24 and 451), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35526.4 (SEQ ID NOs: 25 and 452), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35532.4 (SEQ ID NOs: 26 and 453), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35538.4 (SEQ ID NOs: 27 and 454), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35544.4 (SEQ ID NOs: 28 and 455), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35550.4 (SEQ ID NOs: 29 and 456), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35556.4 (SEQ ID NOs: 30 and 457), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35562.4 (SEQ ID NOs: 31 and 458), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35568.4 (SEQ ID NOs: 32 and 459), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35527.4 (SEQ ID NOs: 33 and 460), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35533.4 (SEQ ID NOs: 34 and 461), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35539.4 (SEQ ID NOs: 35 and 462), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35545.4 (SEQ ID NOs: 36 and 463), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35551.4 (SEQ ID NOs: 37 and 464), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35563.4 (SEQ ID NOs: 38 and 465), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35528.4 (SEQ ID NOs: 39 and 466), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35540.4 (SEQ ID NOs: 40 and 467), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35546.4 (SEQ ID NOs: 41 and 468), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35552.4 (SEQ ID NOs: 42 and 469), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35558.4 (SEQ ID NOs: 43 and 470), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35564.4 (SEQ ID NOs: 44 and 471), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35570.4 (SEQ ID NOs: 45 and 472), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35571.4 (SEQ ID NOs: 46 and 473), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35577.4 (SEQ ID NOs: 47 and 474), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35583.4 (SEQ ID NOs: 48 and 475), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35589.4 (SEQ ID NOs: 49 and 476), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35595.4 (SEQ ID NOs: 50 and 477), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35601.4 (SEQ ID NOs: 51 and 478), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35607.4 (SEQ ID NOs: 52 and 479), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35613.4 (SEQ ID NOs: 53 and 480), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35572.4 (SEQ ID NOs: 54 and 481), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35578.4 (SEQ ID NOs: 55 and 482), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35584.4 (SEQ ID NOs: 56 and 483), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35590.4 (SEQ ID NOs: 57 and 484), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35596.4 (SEQ ID NOs: 58 and 485), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35602.4 (SEQ ID NOs: 59 and 486), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35608.4 (SEQ ID NOs: 60 and 487), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35614.4 (SEQ ID NOs: 61 and 488), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35573.4 (SEQ ID NOs: 62 and 489), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35579.4 (SEQ ID NOs: 63 and 490), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35585.4 (SEQ ID NOs: 64 and 491), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35591.4 (SEQ ID NOs: 65 and 492), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35597.4 (SEQ ID NOs: 66 and 493), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35603.4 (SEQ ID NOs: 67 and 494), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35609.4 (SEQ ID NOs: 68 and 495), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35615.4 (SEQ ID NOs: 69 and 496), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35574.4 (SEQ ID NOs: 70 and 497), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35580.1 (SEQ ID NOs: 71 and 498), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35586.4 (SEQ ID NOs: 72 and 499), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35592.4 (SEQ ID NOs: 73 and 500), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35598.4 (SEQ ID NOs: 74 and 501), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35604.4 (SEQ ID NOs: 75 and 502), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35610.4 (SEQ ID NOs: 76 and 503), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35616.4 (SEQ ID NOs: 77 and 504), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35575.4 (SEQ ID NOs: 78 and 505), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35581.4 (SEQ ID NOs: 79 and 506), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35587.4 (SEQ ID NOs: 80 and 507), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35593.4 (SEQ ID NOs: 81 and 508), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35599.4 (SEQ ID NOs: 82 and 509), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35605.4 (SEQ ID NOs: 83 and 510), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35611.4 (SEQ ID NOs: 84 and 511), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35617.4 (SEQ ID NOs: 85 and 512), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35576.4 (SEQ ID NOs: 86 and 513), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35588.4 (SEQ ID NOs: 87 and 514), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35667.1 (SEQ ID NOs: 88 and 515), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35673.1 (SEQ ID NOs: 89 and 516), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35679.1 (SEQ ID NOs: 90 and 517), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35685.1 (SEQ ID NOs: 91 and 518), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35691.1 (SEQ ID NOs: 92 and 519), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35557.1 (SEQ ID NOs: 93 and 520), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35618.1 (SEQ ID NOs: 94 and 521), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35569.1 (SEQ ID NOs: 95 and 522), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35534.1 (SEQ ID NOs: 96 and 523), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35582.1 (SEQ ID NOs: 97 and 524), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35594.1 (SEQ ID NOs: 98 and 525), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35600.1 (SEQ ID NOs: 99 and 526), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35606.1 (SEQ ID NOs: 100 and 527), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35612.1 (SEQ ID NOs: 101 and 528), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38127.1 (SEQ ID NOs: 102 and 529), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38133.1 (SEQ ID NOs: 103 and 530), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38139.1 (SEQ ID NOs: 104 and 531), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38145.1 (SEQ ID NOs: 105 and 532), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38151.1 (SEQ ID NOs: 106 and 533), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38157.1 (SEQ ID NOs: 107 and 534), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38163.1 (SEQ ID NOs: 108 and 535), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38169.1 (SEQ ID NOs: 109 and 536), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38128.1 (SEQ ID NOs: 110 and 537), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38134.1 (SEQ ID NOs: 111 and 538), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38140.1 (SEQ ID NOs: 112 and 539), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38146.1 (SEQ ID NOs: 113 and 540), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38152.1 (SEQ ID NOs: 114 and 541), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38158.1 (SEQ ID NOs: 115 and 542), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38164.1 (SEQ ID NOs: 116 and 543), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38170.1 (SEQ ID NOs: 117 and 544), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38129.1 (SEQ ID NOs: 118 and 545), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38135.1 (SEQ ID NOs: 119 and 546), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38141.1 (SEQ ID NOs: 120 and 547), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38147.1 (SEQ ID NOs: 121 and 548), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38153.1 (SEQ ID NOs: 122 and 549), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38159.1 (SEQ ID NOs: 123 and 550), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38165.1 (SEQ ID NOs: 124 and 551), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38171.1 (SEQ ID NOs: 125 and 552), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38130.1 (SEQ ID NOs: 126 and 553), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38136.1 (SEQ ID NOs: 127 and 554), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38142.1 (SEQ ID NOs: 128 and 555), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38148.1 (SEQ ID NOs: 129 and 556), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38154.1 (SEQ ID NOs: 130 and 557), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38160.1 (SEQ ID NOs: 131 and 558), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38166.1 (SEQ ID NOs: 132 and 559), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38172.1 (SEQ ID NOs: 133 and 560), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38131.1 (SEQ ID NOs: 134 and 561), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38137.1 (SEQ ID NOs: 135 and 562), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38143.1 (SEQ ID NOs: 136 and 563), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38149.1 (SEQ ID NOs: 137 and 564), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38155.1 (SEQ ID NOs: 138 and 565), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38161.1 (SEQ ID NOs: 139 and 566), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38167.1 (SEQ ID NOs: 140 and 567), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38173.1 (SEQ ID NOs: 141 and 568), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38132.1 (SEQ ID NOs: 142 and 569), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38138.1 (SEQ ID NOs: 143 and 570), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38144.1 (SEQ ID NOs: 144 and 571), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38150.1 (SEQ ID NOs: 145 and 572), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38156.1 (SEQ ID NOs: 146 and 573), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38162.1 (SEQ ID NOs: 147 and 574), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38168.1 (SEQ ID NOs: 148 and 575), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38174.1 (SEQ ID NOs: 149 and 576), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39683.1 (SEQ ID NOs: 150 and 577), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39689.1 (SEQ ID NOs: 151 and 578), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39695.1 (SEQ ID NOs: 152 and 579), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39701.1 (SEQ ID NOs: 153 and 580), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39707.1 (SEQ ID NOs: 154 and 581), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39713.1 (SEQ ID NOs: 155 and 582), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39719.1 (SEQ ID NOs: 156 and 583), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39725.1 (SEQ ID NOs: 157 and 584), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39684.1 (SEQ ID NOs: 158 and 585), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39690.1 (SEQ ID NOs: 159 and 586), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39696.1 (SEQ ID NOs: 160 and 587), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39702.1 (SEQ ID NOs: 161 and 588), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39708.1 (SEQ ID NOs: 162 and 589), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39714.1 (SEQ ID NOs: 163 and 590), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39720.1 (SEQ ID NOs: 164 and 591), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39726.1 (SEQ ID NOs: 165 and 592), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39685.1 (SEQ ID NOs: 166 and 593), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39691.1 (SEQ ID NOs: 167 and 594), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39697.1 (SEQ ID NOs: 168 and 595), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39703.1 (SEQ ID NOs: 169 and 596), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39709.1 (SEQ ID NOs: 170 and 597), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39715.1 (SEQ ID NOs: 171 and 598), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39721.1 (SEQ ID NOs: 172 and 599), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39727.1 (SEQ ID NOs: 173 and 600), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39686.1 (SEQ ID NOs: 174 and 601), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39692.1 (SEQ ID NOs: 175 and 602), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39698.1 (SEQ ID NOs: 176 and 603), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39704.1 (SEQ ID NOs: 177 and 604), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39710.1 (SEQ ID NOs: 178 and 605), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39716.1 (SEQ ID NOs: 179 and 606), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39722.1 (SEQ ID NOs: 180 and 607), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39728.1 (SEQ ID NOs: 181 and 608), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39687.1 (SEQ ID NOs: 182 and 609), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39693.1 (SEQ ID NOs: 183 and 610), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39699.1 (SEQ ID NOs: 184 and 611), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39705.1 (SEQ ID NOs: 185 and 612), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39711.1 (SEQ ID NOs: 186 and 613), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39717.1 (SEQ ID NOs: 187 and 614), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39723.1 (SEQ ID NOs: 188 and 615), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39729.1 (SEQ ID NOs: 189 and 616), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39688.1 (SEQ ID NOs: 190 and 617), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39694.1 (SEQ ID NOs: 191 and 618), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39700.1 (SEQ ID NOs: 192 and 619), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39706.1 (SEQ ID NOs: 193 and 620), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39712.1 (SEQ ID NOs: 194 and 621), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39718.1 (SEQ ID NOs: 195 and 622), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39724.1 (SEQ ID NOs: 196 and 623), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39730.1 (SEQ ID NOs: 197 and 624), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39736.1 (SEQ ID NOs: 198 and 625), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39742.1 (SEQ ID NOs: 199 and 626), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39748.1 (SEQ ID NOs: 200 and 627), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39754.1 (SEQ ID NOs: 201 and 628), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39760.1 (SEQ ID NOs: 202 and 629), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39766.1 (SEQ ID NOs: 203 and 630), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39772.1 (SEQ ID NOs: 204 and 631), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39731.1 (SEQ ID NOs: 205 and 632), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39737.1 (SEQ ID NOs: 206 and 633), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39743.1 (SEQ ID NOs: 207 and 634), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39749.1 (SEQ ID NOs: 208 and 635), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39755.1 (SEQ ID NOs: 209 and 636), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39761.1 (SEQ ID NOs: 210 and 637), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39767.1 (SEQ ID NOs: 211 and 638), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39773.1 (SEQ ID NOs: 212 and 639), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39732.1 (SEQ ID NOs: 213 and 640), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39738.1 (SEQ ID NOs: 214 and 641), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39744.1 (SEQ ID NOs: 215 and 642), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39750.1 (SEQ ID NOs: 216 and 643), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39756.1 (SEQ ID NOs: 217 and 644), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39762.1 (SEQ ID NOs: 218 and 645), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39768.1 (SEQ ID NOs: 219 and 646), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39774.1 (SEQ ID NOs: 220 and 647), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39733.1 (SEQ ID NOs: 221 and 648), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39739.1 (SEQ ID NOs: 222 and 649), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39745.1 (SEQ ID NOs: 223 and 650), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39751.1 (SEQ ID NOs: 224 and 651), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39757.1 (SEQ ID NOs: 225 and 652), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39763.1 (SEQ ID NOs: 226 and 653), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39769.1 (SEQ ID NOs: 227 and 654), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39775.1 (SEQ ID NOs: 228 and 655), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39734.1 (SEQ ID NOs: 229 and 656), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39740.1 (SEQ ID NOs: 230 and 657), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39746.1 (SEQ ID NOs: 231 and 658), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39752.1 (SEQ ID NOs: 232 and 659), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39758.1 (SEQ ID NOs: 233 and 660), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39764.1 (SEQ ID NOs: 234 and 661), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39770.1 (SEQ ID NOs: 235 and 662), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39776.1 (SEQ ID NOs: 236 and 663), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39735.1 (SEQ ID NOs: 237 and 664), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39741.1 (SEQ ID NOs: 238 and 665), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39747.1 (SEQ ID NOs: 239 and 666), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39753.1 (SEQ ID NOs: 240 and 667), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39759.1 (SEQ ID NOs: 241 and 668), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39765.1 (SEQ ID NOs: 242 and 669), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39771.1 (SEQ ID NOs: 243 and 670), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39778.1 (SEQ ID NOs: 244 and 671), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39784.1 (SEQ ID NOs: 245 and 672), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39790.1 (SEQ ID NOs: 246 and 673), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39796.1 (SEQ ID NOs: 247 and 674), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39802.1 (SEQ ID NOs: 248 and 675), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39808.1 (SEQ ID NOs: 249 and 676), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39814.1 (SEQ ID NOs: 250 and 677), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39820.1 (SEQ ID NOs: 251 and 678), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39779.1 (SEQ ID NOs: 252 and 679), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39785.1 (SEQ ID NOs: 253 and 680), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39791.1 (SEQ ID NOs: 254 and 681), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39797.1 (SEQ ID NOs: 255 and 682), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39803.1 (SEQ ID NOs: 256 and 683), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39809.1 (SEQ ID NOs: 257 and 684), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39815.1 (SEQ ID NOs: 258 and 685), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39821.1 (SEQ ID NOs: 259 and 686), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39780.1 (SEQ ID NOs: 260 and 687), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39786.1 (SEQ ID NOs: 261 and 688), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39792.1 (SEQ ID NOs: 262 and 689), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39798.1 (SEQ ID NOs: 263 and 690), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39804.1 (SEQ ID NOs: 264 and 691), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39810.1 (SEQ ID NOs: 265 and 692), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39816.1 (SEQ ID NOs: 266 and 693), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39822.1 (SEQ ID NOs: 267 and 694), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39781.1 (SEQ ID NOs: 268 and 695), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39787.1 (SEQ ID NOs: 269 and 696), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39793.1 (SEQ ID NOs: 270 and 697), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39799.1 (SEQ ID NOs: 271 and 698), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39805.1 (SEQ ID NOs: 272 and 699), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39811.1 (SEQ ID NOs: 273 and 700), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39817.1 (SEQ ID NOs: 274 and 701), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39823.1 (SEQ ID NOs: 275 and 702), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39782.1 (SEQ ID NOs: 276 and 703), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39788.1 (SEQ ID NOs: 277 and 704), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39794.1 (SEQ ID NOs: 278 and 705), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39800.1 (SEQ ID NOs: 279 and 706), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39806.1 (SEQ ID NOs: 280 and 707), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39812.1 (SEQ ID NOs: 281 and 708), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39818.1 (SEQ ID NOs: 282 and 709), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39824.1 (SEQ ID NOs: 283 and 710), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39783.1 (SEQ ID NOs: 284 and 711), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39789.1 (SEQ ID NOs: 285 and 712), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39795.1 (SEQ ID NOs: 286 and 713), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39801.1 (SEQ ID NOs: 287 and 714), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39807.1 (SEQ ID NOs: 288 and 715), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39813.1 (SEQ ID NOs: 289 and 716), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39819.1 (SEQ ID NOs: 290 and 717), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39825.1 (SEQ ID NOs: 291 and 718), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39831.1 (SEQ ID NOs: 292 and 719), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39837.1 (SEQ ID NOs: 293 and 720), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39843.1 (SEQ ID NOs: 294 and 721), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39849.1 (SEQ ID NOs: 295 and 722), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39855.1 (SEQ ID NOs: 296 and 723), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39861.1 (SEQ ID NOs: 297 and 724), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39867.1 (SEQ ID NOs: 298 and 725), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39826.1 (SEQ ID NOs: 299 and 726), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39832.1 (SEQ ID NOs: 300 and 727), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39838.1 (SEQ ID NOs: 301 and 728), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39844.1 (SEQ ID NOs: 302 and 729), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39850.1 (SEQ ID NOs: 303 and 730), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39856.1 (SEQ ID NOs: 304 and 731), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39862.1 (SEQ ID NOs: 305 and 732), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39868.1 (SEQ ID NOs: 306 and 733), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39827.1 (SEQ ID NOs: 307 and 734), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39833.1 (SEQ ID NOs: 308 and 735), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39839.1 (SEQ ID NOs: 309 and 736), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39845.1 (SEQ ID NOs: 310 and 737), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39851.1 (SEQ ID NOs: 311 and 738), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39857.1 (SEQ ID NOs: 312 and 739), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39863.1 (SEQ ID NOs: 313 and 740), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39869.1 (SEQ ID NOs: 314 and 741), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39828.1 (SEQ ID NOs: 315 and 742), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39834.1 (SEQ ID NOs: 316 and 743), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39840.1 (SEQ ID NOs: 317 and 744), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39846.1 (SEQ ID NOs: 318 and 745), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39852.1 (SEQ ID NOs: 319 and 746), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39858.1 (SEQ ID NOs: 320 and 747), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39864.1 (SEQ ID NOs: 321 and 748), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39870.1 (SEQ ID NOs: 322 and 749), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39829.1 (SEQ ID NOs: 323 and 750), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39835.1 (SEQ ID NOs: 324 and 751), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39841.1 (SEQ ID NOs: 325 and 752), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39853.1 (SEQ ID NOs: 326 and 753), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39859.1 (SEQ ID NOs: 327 and 754), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39865.1 (SEQ ID NOs: 328 and 755), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39871.1 (SEQ ID NOs: 329 and 756), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39830.1 (SEQ ID NOs: 330 and 757), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39836.1 (SEQ ID NOs: 331 and 758), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39842.1 (SEQ ID NOs: 332 and 759), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39848.1 (SEQ ID NOs: 333 and 760), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39854.1 (SEQ ID NOs: 334 and 761), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39860.1 (SEQ ID NOs: 335 and 762), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39866.1 (SEQ ID NOs: 336 and 763), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39992.1 (SEQ ID NOs: 337 and 764), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39998.1 (SEQ ID NOs: 338 and 765), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40004.1 (SEQ ID NOs: 339 and 766), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40010.1 (SEQ ID NOs: 340 and 767), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40016.1 (SEQ ID NOs: 341 and 768), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40022.1 (SEQ ID NOs: 342 and 769), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40028.1 (SEQ ID NOs: 343 and 770), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40034.1 (SEQ ID NOs: 344 and 771), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39999.1 (SEQ ID NOs: 345 and 772), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40005.1 (SEQ ID NOs: 346 and 773), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40011.1 (SEQ ID NOs: 347 and 774), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40017.1 (SEQ ID NOs: 348 and 775), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40029.1 (SEQ ID NOs: 349 and 776), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40035.1 (SEQ ID NOs: 350 and 777), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39994.1 (SEQ ID NOs: 351 and 778), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40000.1 (SEQ ID NOs: 352 and 779), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40006.1 (SEQ ID NOs: 353 and 780), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40012.1 (SEQ ID NOs: 354 and 781), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40018.1 (SEQ ID NOs: 355 and 782), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40024.1 (SEQ ID NOs: 356 and 783), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40030.1 (SEQ ID NOs: 357 and 784), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40036.1 (SEQ ID NOs: 358 and 785), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39995.1 (SEQ ID NOs: 359 and 786), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40001.1 (SEQ ID NOs: 360 and 787), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40007.1 (SEQ ID NOs: 361 and 788), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40013.1 (SEQ ID NOs: 362 and 789), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40019.1 (SEQ ID NOs: 363 and 790), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40025.1 (SEQ ID NOs: 364 and 791), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40031.1 (SEQ ID NOs: 365 and 792), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40037.1 (SEQ ID NOs: 366 and 793), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39996.1 (SEQ ID NOs: 367 and 794), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40002.1 (SEQ ID NOs: 368 and 795), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40008.1 (SEQ ID NOs: 369 and 796), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40014.1 (SEQ ID NOs: 370 and 797), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40020.1 (SEQ ID NOs: 371 and 798), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40026.1 (SEQ ID NOs: 372 and 799), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40032.1 (SEQ ID NOs: 373 and 800), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40038.1 (SEQ ID NOs: 374 and 801), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39997.1 (SEQ ID NOs: 375 and 802), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40009.1 (SEQ ID NOs: 376 and 803), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40015.1 (SEQ ID NOs: 377 and 804), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40021.1 (SEQ ID NOs: 378 and 805), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40027.1 (SEQ ID NOs: 379 and 806), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40033.1 (SEQ ID NOs: 380 and 807), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40039.1 (SEQ ID NOs: 381 and 808), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40045.1 (SEQ ID NOs: 382 and 809), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40051.1 (SEQ ID NOs: 383 and 810), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40057.1 (SEQ ID NOs: 384 and 811), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40063.1 (SEQ ID NOs: 385 and 812), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40069.1 (SEQ ID NOs: 386 and 813), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40075.1 (SEQ ID NOs: 387 and 814), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40081.1 (SEQ ID NOs: 388 and 815), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40040.1 (SEQ ID NOs: 389 and 816), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40046.1 (SEQ ID NOs: 390 and 817), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40052.1 (SEQ ID NOs: 391 and 818), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40058.1 (SEQ ID NOs: 392 and 819), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40064.1 (SEQ ID NOs: 393 and 820), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40070.1 (SEQ ID NOs: 394 and 821), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40076.1 (SEQ ID NOs: 395 and 822), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40082.1 (SEQ ID NOs: 396 and 823), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40041.1 (SEQ ID NOs: 397 and 824), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40047.1 (SEQ ID NOs: 398 and 825), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40053.1 (SEQ ID NOs: 399 and 826), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40059.1 (SEQ ID NOs: 400 and 827), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40065.1 (SEQ ID NOs: 401 and 828), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40071.1 (SEQ ID NOs: 402 and 829), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40077.1 (SEQ ID NOs: 403 and 830), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40083.1 (SEQ ID NOs: 404 and 831), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40042.1 (SEQ ID NOs: 405 and 832), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40048.1 (SEQ ID NOs: 406 and 833), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40054.1 (SEQ ID NOs: 407 and 834), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40060.1 (SEQ ID NOs: 408 and 835), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40066.1 (SEQ ID NOs: 409 and 836), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40072.1 (SEQ ID NOs: 410 and 837), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40078.1 (SEQ ID NOs: 411 and 838), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40084.1 (SEQ ID NOs: 412 and 839), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40043.1 (SEQ ID NOs: 413 and 840), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40049.1 (SEQ ID NOs: 414 and 841), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40055.1 (SEQ ID NOs: 415 and 842), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40061.1 (SEQ ID NOs: 416 and 843), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40067.1 (SEQ ID NOs: 417 and 844), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40073.1 (SEQ ID NOs: 418 and 845), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40079.1 (SEQ ID NOs: 419 and 846), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40085.1 (SEQ ID NOs: 420 and 847), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40044.1 (SEQ ID NOs: 421 and 848), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40050.1 (SEQ ID NOs: 422 and 849), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40056.1 (SEQ ID NOs: 423 and 850), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40062.1 (SEQ ID NOs: 424 and 851), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40068.1 (SEQ ID NOs: 425 and 852), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40074.1 (SEQ ID NOs: 426 and 853), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40080.1 (SEQ ID NOs: 427 and 854), ora modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39720.1 (SEQ ID NOs: 1716 and 1754),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39706.1 (SEQ ID NOs: 1717 and 1755),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39712.1 (SEQ ID NOs: 1718 and 1756),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39760.1 (SEQ ID NOs: 1719 and 1757),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39732.1 (SEQ ID NOs: 1720 and 1758),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35541.4 (SEQ ID NOs: 1721 and 1759),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39735.1 or hs_KRAS_(—)321_A22S26 (SEQID NOs: 1722 and 1760), or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39741.1, or modified or unmodifiedvariants thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: hs_KRAS_(—) 322_A22S26 (SEQ ID NOs: 1723and 1761), or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39778.1 (SEQ ID NOs: 1724 and 1762),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39790.1 (SEQ ID NOs: 1725 and 1763),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39822.1 (SEQ ID NOs: 1726 and 1764),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35609.4 (SEQ ID NOs: 1727 and 1765),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35581.4 (SEQ ID NOs: 1728 and 1766),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39845.1 (SEQ ID NOs: 1729 and 1767),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39858.1 (SEQ ID NOs: 1730 and 1768),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39870.1 (SEQ ID NOs: 1731 and 1769),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35576.4 (SEQ ID NOs: 1732 and 1770),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35588.4 (SEQ ID NOs: 1733 and 1771),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35600.1 (SEQ ID NOs: 1734 and 1772),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-35606.1 (SEQ ID NOs: 1735 and 1773),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38151.1 (SEQ ID NOs: 1736 and 1774),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38163.1 (SEQ ID NOs: 1737 and 1775),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-39999.1 (SEQ ID NOs: 1738 and 1776),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38159.1 or hs_KRAS_(—)528_A22S26 (SEQID NOs: 1739 and 1777), or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38130.1 or hs_KRAS_(—)531_A22S26 (SEQID NOs: 1740 and 1778), or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38136.1 (SEQ ID NOs: 1741 and 1779),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40036.1 (SEQ ID NOs: 1742 and 1780),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40008.1 (SEQ ID NOs: 1743 and 1781),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40021.1 (SEQ ID NOs: 1744 and 1782),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40077.1 (SEQ ID NOs: 1745 and 1783),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40072.1 (SEQ ID NOs: 1746 and 1784),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40061.1 (SEQ ID NOs: 1747 and 1785),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-40068.1 (SEQ ID NOs: 1748 and 1786),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38131.1 (SEQ ID NOs: 1749 and 1787),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: AD-38167.1 (SEQ ID NOs: 1750 and 1788),or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: hs_KRAS 1273_A22S26 (SEQ ID NOs: 1751and 1789), or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: hs_KRAS 2892_A37S26 (SEQ ID NOs: 1752and 1790), or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequences of the first and/or second strands are the sequences of thefirst and/or second strands of: hs_KRAS 4731_A22S26 (SEQ ID NOs: 1753and 1791), or a modified or unmodified variant thereof.

Specific embodiments wherein the sequences of the first and/or secondstrands are the sequences of the first and/or second strand of a RNAiagent disclosed herein, further comprising up to about 20 additionalnucleotides

In one embodiment, the present disclosure pertains to a compositioncomprising any one or more of: a RNAi agent comprising a first and asecond strand, wherein the sequence of the first and/or second strand isthe sequence of a first and/or second strand of any RNAi agent from anyof Tables 1 to 6, or modified and unmodified variants thereof, whereinthe first and/or second strand further comprise up to about 20additional nucleotides, wherein the first and/or second strand furthercomprise up to about 20 additional nucleotides.

Thus, in various embodiments, the present disclosure pertains to acomposition comprising any one or more of the following:

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35523.3 (SEQ ID NOs: 1 and 428), or modifiedor unmodified variants thereof, wherein the first and/or second strandfurther comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35529.1 (SEQ ID NOs: 2 and 429), or modifiedor unmodified variants thereof, wherein the first and/or second strandfurther comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35535.4 (SEQ ID NOs: 3 and 430), or modifiedor unmodified variants thereof, wherein the first and/or second strandfurther comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35541.4 (SEQ ID NOs: 4 and 431), or modifiedor unmodified variants thereof, wherein the first and/or second strandfurther comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35547.4 (SEQ ID NOs: 5 and 432), or modifiedor unmodified variants thereof, wherein the first and/or second strandfurther comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35553.4 (SEQ ID NOs: 6 and 433), or modifiedor unmodified variants thereof, wherein the first and/or second strandfurther comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35559.4 (SEQ ID NOs: 7 and 434), or modifiedor unmodified variants thereof, wherein the first and/or second strandfurther comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35565.4 (SEQ ID NOs: 8 and 435), or modifiedor unmodified variants thereof, wherein the first and/or second strandfurther comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35524.4 (SEQ ID NOs: 9 and 436), or modifiedor unmodified variants thereof, wherein the first and/or second strandfurther comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35530.4 (SEQ ID NOs: and 437), or modifiedor unmodified variants thereof, wherein the first and/or second strandfurther comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35536.4 (SEQ ID NOs: 11 and 438), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35542.4 (SEQ ID NOs: 12 and 439), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35548.4 (SEQ ID NOs: 13 and 440), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35554.4 (SEQ ID NOs: 14 and 441), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35560.2 (SEQ ID NOs: 15 and 442), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35566.4 (SEQ ID NOs: 16 and 443), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35525.2 (SEQ ID NOs: 17 and 444), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35531.4 (SEQ ID NOs: 18 and 445), ormodified or unmodified variants thereof, wherein the first and/or secondstrand

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35537.4 (SEQ ID NOs: 19 and 446), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35543.2 (SEQ ID NOs: 20 and 447), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35549.4 (SEQ ID NOs: 21 and 448), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35555.4 (SEQ ID NOs: 22 and 449), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35561.4 (SEQ ID NOs: 23 and 450), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35567.4 (SEQ ID NOs: 24 and 451), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35526.4 (SEQ ID NOs: 25 and 452), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35532.4 (SEQ ID NOs: 26 and 453), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35538.4 (SEQ ID NOs: 27 and 454), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35544.4 (SEQ ID NOs: 28 and 455), ormodified or unmodified variants thereof, wherein the first and/or secondstrand

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35550.4 (SEQ ID NOs: 29 and 456), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35556.4 (SEQ ID NOs: 30 and 457), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35562.4 (SEQ ID NOs: 31 and 458), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35568.4 (SEQ ID NOs: 32 and 459), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35527.4 (SEQ ID NOs: 33 and 460), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35533.4 (SEQ ID NOs: 34 and 461), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35539.4 (SEQ ID NOs: 35 and 462), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35545.4 (SEQ ID NOs: 36 and 463), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35551.4 (SEQ ID NOs: 37 and 464), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35563.4 (SEQ ID NOs: 38 and 465), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35528.4 (SEQ ID NOs: 39 and 466), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35540.4 (SEQ ID NOs: 40 and 467), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35546.4 (SEQ ID NOs: 41 and 468), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35552.4 (SEQ ID NOs: 42 and 469), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35558.4 (SEQ ID NOs: 43 and 470), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35564.4 (SEQ ID NOs: 44 and 471), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35570.4 (SEQ ID NOs: 45 and 472), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35571.4 (SEQ ID NOs: 46 and 473), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35577.4 (SEQ ID NOs: 47 and 474), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35583.4 (SEQ ID NOs: 48 and 475), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35589.4 (SEQ ID NOs: 49 and 476), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35595.4 (SEQ ID NOs: 50 and 477), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35601.4 (SEQ ID NOs: 51 and 478), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35607.4 (SEQ ID NOs: 52 and 479), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35613.4 (SEQ ID NOs: 53 and 480), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35572.4 (SEQ ID NOs: 54 and 481), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35578.4 (SEQ ID NOs: 55 and 482), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35584.4 (SEQ ID NOs: 56 and 483), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35590.4 (SEQ ID NOs: 57 and 484), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35596.4 (SEQ ID NOs: 58 and 485), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35602.4 (SEQ ID NOs: 59 and 486), ormodified or unmodified variants thereof, wherein the first and/or secondstrand

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35608.4 (SEQ ID NOs: 60 and 487), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35614.4 (SEQ ID NOs: 61 and 488), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35573.4 (SEQ ID NOs: 62 and 489), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35579.4 (SEQ ID NOs: 63 and 490), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35585.4 (SEQ ID NOs: 64 and 491), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35591.4 (SEQ ID NOs: 65 and 492), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35597.4 (SEQ ID NOs: 66 and 493), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35603.4 (SEQ ID NOs: 67 and 494), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35609.4 (SEQ ID NOs: 68 and 495), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35615.4 (SEQ ID NOs: 69 and 496), ormodified or unmodified variants thereof, wherein the first and/or secondstrand

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35574.4 (SEQ ID NOs: 70 and 497), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35580.1 (SEQ ID NOs: 71 and 498), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35586.4 (SEQ ID NOs: 72 and 499), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35592.4 (SEQ ID NOs: 73 and 500), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35598.4 (SEQ ID NOs: 74 and 501), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35604.4 (SEQ ID NOs: 75 and 502), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35610.4 (SEQ ID NOs: 76 and 503), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35616.4 (SEQ ID NOs: 77 and 504), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35575.4 (SEQ ID NOs: 78 and 505), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35581.4 (SEQ ID NOs: 79 and 506), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35587.4 (SEQ ID NOs: 80 and 507), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35593.4 (SEQ ID NOs: 81 and 508), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35599.4 (SEQ ID NOs: 82 and 509), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35605.4 (SEQ ID NOs: 83 and 510), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35611.4 (SEQ ID NOs: 84 and 511), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35617.4 (SEQ ID NOs: 85 and 512), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35576.4 (SEQ ID NOs: 86 and 513), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35588.4 (SEQ ID NOs: 87 and 514), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35667.1 (SEQ ID NOs: 88 and 515), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35673.1 (SEQ ID NOs: 89 and 516), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35679.1 (SEQ ID NOs: 90 and 517), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35685.1 (SEQ ID NOs: 91 and 518), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35691.1 (SEQ ID NOs: 92 and 519), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35557.1 (SEQ ID NOs: 93 and 520), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35618.1 (SEQ ID NOs: 94 and 521), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35569.1 (SEQ ID NOs: 95 and 522), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35534.1 (SEQ ID NOs: 96 and 523), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35582.1 (SEQ ID NOs: 97 and 524), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35594.1 (SEQ ID NOs: 98 and 525), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35600.1 (SEQ ID NOs: 99 and 526), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35606.1 (SEQ ID NOs: 100 and 527), ormodified or unmodified variants thereof, wherein the first and/or secondstrand

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35612.1 (SEQ ID NOs: 101 and 528), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38127.1 (SEQ ID NOs: 102 and 529), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38133.1 (SEQ ID NOs: 103 and 530), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38139.1 (SEQ ID NOs: 104 and 531), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38145.1 (SEQ ID NOs: 105 and 532), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38151.1 (SEQ ID NOs: 106 and 533), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38157.1 (SEQ ID NOs: 107 and 534), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38163.1 (SEQ ID NOs: 108 and 535), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38169.1 (SEQ ID NOs: 109 and 536), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38128.1 (SEQ ID NOs: 110 and 537), ormodified or unmodified variants thereof, wherein the first and/or secondstrand

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38134.1 (SEQ ID NOs: 111 and 538), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38140.1 (SEQ ID NOs: 112 and 539), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38146.1 (SEQ ID NOs: 113 and 540), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38152.1 (SEQ ID NOs: 114 and 541), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38158.1 (SEQ ID NOs: 115 and 542), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38164.1 (SEQ ID NOs: 116 and 543), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38170.1 (SEQ ID NOs: 117 and 544), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38129.1 (SEQ ID NOs: 118 and 545), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38135.1 (SEQ ID NOs: 119 and 546), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38141.1 (SEQ ID NOs: 120 and 547), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38147.1 (SEQ ID NOs: 121 and 548), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38153.1 (SEQ ID NOs: 122 and 549), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38159.1 (SEQ ID NOs: 123 and 550), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38165.1 (SEQ ID NOs: 124 and 551), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38171.1 (SEQ ID NOs: 125 and 552), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38130.1 (SEQ ID NOs: 126 and 553), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38136.1 (SEQ ID NOs: 127 and 554), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38142.1 (SEQ ID NOs: 128 and 555), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38148.1 (SEQ ID NOs: 129 and 556), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38154.1 (SEQ ID NOs: 130 and 557), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38160.1 (SEQ ID NOs: 131 and 558), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38166.1 (SEQ ID NOs: 132 and 559), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38172.1 (SEQ ID NOs: 133 and 560), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38131.1 (SEQ ID NOs: 134 and 561), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38137.1 (SEQ ID NOs: 135 and 562), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38143.1 (SEQ ID NOs: 136 and 563), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38149.1 (SEQ ID NOs: 137 and 564), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38155.1 (SEQ ID NOs: 138 and 565), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38161.1 (SEQ ID NOs: 139 and 566), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38167.1 (SEQ ID NOs: 140 and 567), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38173.1 (SEQ ID NOs: 141 and 568), ormodified or unmodified variants thereof, wherein the first and/or secondstrand

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38132.1 (SEQ ID NOs: 142 and 569), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38138.1 (SEQ ID NOs: 143 and 570), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38144.1 (SEQ ID NOs: 144 and 571), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38150.1 (SEQ ID NOs: 145 and 572), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38156.1 (SEQ ID NOs: 146 and 573), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38162.1 (SEQ ID NOs: 147 and 574), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38168.1 (SEQ ID NOs: 148 and 575), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38174.1 (SEQ ID NOs: 149 and 576), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39683.1 (SEQ ID NOs: 150 and 577), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39689.1 (SEQ ID NOs: 151 and 578), ormodified or unmodified variants thereof, wherein the first and/or secondstrand

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39695.1 (SEQ ID NOs: 152 and 579), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39701.1 (SEQ ID NOs: 153 and 580), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39707.1 (SEQ ID NOs: 154 and 581), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39713.1 (SEQ ID NOs: 155 and 582), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39719.1 (SEQ ID NOs: 156 and 583), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39725.1 (SEQ ID NOs: 157 and 584), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39684.1 (SEQ ID NOs: 158 and 585), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39690.1 (SEQ ID NOs: 159 and 586), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39696.1 (SEQ ID NOs: 160 and 587), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39702.1 (SEQ ID NOs: 161 and 588), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39708.1 (SEQ ID NOs: 162 and 589), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39714.1 (SEQ ID NOs: 163 and 590), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39720.1 (SEQ ID NOs: 164 and 591), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39726.1 (SEQ ID NOs: 165 and 592), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39685.1 (SEQ ID NOs: 166 and 593), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39691.1 (SEQ ID NOs: 167 and 594), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39697.1 (SEQ ID NOs: 168 and 595), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39703.1 (SEQ ID NOs: 169 and 596), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39709.1 (SEQ ID NOs: 170 and 597), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39715.1 (SEQ ID NOs: 171 and 598), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39721.1 (SEQ ID NOs: 172 and 599), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39727.1 (SEQ ID NOs: 173 and 600), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39686.1 (SEQ ID NOs: 174 and 601), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39692.1 (SEQ ID NOs: 175 and 602), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39698.1 (SEQ ID NOs: 176 and 603), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39704.1 (SEQ ID NOs: 177 and 604), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39710.1 (SEQ ID NOs: 178 and 605), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39716.1 (SEQ ID NOs: 179 and 606), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39722.1 (SEQ ID NOs: 180 and 607), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39728.1 (SEQ ID NOs: 181 and 608), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39687.1 (SEQ ID NOs: 182 and 609), ormodified or unmodified variants thereof, wherein the first and/or secondstrand

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39693.1 (SEQ ID NOs: 183 and 610), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39699.1 (SEQ ID NOs: 184 and 611), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39705.1 (SEQ ID NOs: 185 and 612), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39711.1 (SEQ ID NOs: 186 and 613), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39717.1 (SEQ ID NOs: 187 and 614), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39723.1 (SEQ ID NOs: 188 and 615), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39729.1 (SEQ ID NOs: 189 and 616), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39688.1 (SEQ ID NOs: 190 and 617), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39694.1 (SEQ ID NOs: 191 and 618), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39700.1 (SEQ ID NOs: 192 and 619), ormodified or unmodified variants thereof, wherein the first and/or secondstrand

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39706.1 (SEQ ID NOs: 193 and 620), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39712.1 (SEQ ID NOs: 194 and 621), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39718.1 (SEQ ID NOs: 195 and 622), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39724.1 (SEQ ID NOs: 196 and 623), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39730.1 (SEQ ID NOs: 197 and 624), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39736.1 (SEQ ID NOs: 198 and 625), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39742.1 (SEQ ID NOs: 199 and 626), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39748.1 (SEQ ID NOs: 200 and 627), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39754.1 (SEQ ID NOs: 201 and 628), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39760.1 (SEQ ID NOs: 202 and 629), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39766.1 (SEQ ID NOs: 203 and 630), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39772.1 (SEQ ID NOs: 204 and 631), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39731.1 (SEQ ID NOs: 205 and 632), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39737.1 (SEQ ID NOs: 206 and 633), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39743.1 (SEQ ID NOs: 207 and 634), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39749.1 (SEQ ID NOs: 208 and 635), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39755.1 (SEQ ID NOs: 209 and 636), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39761.1 (SEQ ID NOs: 210 and 637), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39767.1 (SEQ ID NOs: 211 and 638), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39773.1 (SEQ ID NOs: 212 and 639), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39732.1 (SEQ ID NOs: 213 and 640), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39738.1 (SEQ ID NOs: 214 and 641), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39744.1 (SEQ ID NOs: 215 and 642), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39750.1 (SEQ ID NOs: 216 and 643), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39756.1 (SEQ ID NOs: 217 and 644), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39762.1 (SEQ ID NOs: 218 and 645), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39768.1 (SEQ ID NOs: 219 and 646), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39774.1 (SEQ ID NOs: 220 and 647), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39733.1 (SEQ ID NOs: 221 and 648), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39739.1 (SEQ ID NOs: 222 and 649), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39745.1 (SEQ ID NOs: 223 and 650), ormodified or unmodified variants thereof, wherein the first and/or secondstrand

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39751.1 (SEQ ID NOs: 224 and 651), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39757.1 (SEQ ID NOs: 225 and 652), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39763.1 (SEQ ID NOs: 226 and 653), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39769.1 (SEQ ID NOs: 227 and 654), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39775.1 (SEQ ID NOs: 228 and 655), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39734.1 (SEQ ID NOs: 229 and 656), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39740.1 (SEQ ID NOs: 230 and 657), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39746.1 (SEQ ID NOs: 231 and 658), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39752.1 (SEQ ID NOs: 232 and 659), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39758.1 (SEQ ID NOs: 233 and 660), ormodified or unmodified variants thereof, wherein the first and/or secondstrand

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39764.1 (SEQ ID NOs: 234 and 661), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39770.1 (SEQ ID NOs: 235 and 662), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39776.1 (SEQ ID NOs: 236 and 663), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39735.1 (SEQ ID NOs: 237 and 664), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39741.1 (SEQ ID NOs: 238 and 665), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39747.1 (SEQ ID NOs: 239 and 666), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39753.1 (SEQ ID NOs: 240 and 667), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39759.1 (SEQ ID NOs: 241 and 668), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39765.1 (SEQ ID NOs: 242 and 669), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39771.1 (SEQ ID NOs: 243 and 670), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39778.1 (SEQ ID NOs: 244 and 671), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39784.1 (SEQ ID NOs: 245 and 672), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39790.1 (SEQ ID NOs: 246 and 673), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39796.1 (SEQ ID NOs: 247 and 674), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39802.1 (SEQ ID NOs: 248 and 675), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39808.1 (SEQ ID NOs: 249 and 676), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39814.1 (SEQ ID NOs: 250 and 677), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39820.1 (SEQ ID NOs: 251 and 678), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39779.1 (SEQ ID NOs: 252 and 679), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39785.1 (SEQ ID NOs: 253 and 680), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39791.1 (SEQ ID NOs: 254 and 681), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39797.1 (SEQ ID NOs: 255 and 682), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39803.1 (SEQ ID NOs: 256 and 683), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39809.1 (SEQ ID NOs: 257 and 684), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39815.1 (SEQ ID NOs: 258 and 685), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39821.1 (SEQ ID NOs: 259 and 686), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39780.1 (SEQ ID NOs: 260 and 687), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39786.1 (SEQ ID NOs: 261 and 688), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39792.1 (SEQ ID NOs: 262 and 689), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39798.1 (SEQ ID NOs: 263 and 690), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39804.1 (SEQ ID NOs: 264 and 691), ormodified or unmodified variants thereof, wherein the first and/or secondstrand

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39810.1 (SEQ ID NOs: 265 and 692), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39816.1 (SEQ ID NOs: 266 and 693), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39822.1 (SEQ ID NOs: 267 and 694), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39781.1 (SEQ ID NOs: 268 and 695), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39787.1 (SEQ ID NOs: 269 and 696), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39793.1 (SEQ ID NOs: 270 and 697), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39799.1 (SEQ ID NOs: 271 and 698), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39805.1 (SEQ ID NOs: 272 and 699), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39811.1 (SEQ ID NOs: 273 and 700), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39817.1 (SEQ ID NOs: 274 and 701), ormodified or unmodified variants thereof, wherein the first and/or secondstrand

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39823.1 (SEQ ID NOs: 275 and 702), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39782.1 (SEQ ID NOs: 276 and 703), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39788.1 (SEQ ID NOs: 277 and 704), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39794.1 (SEQ ID NOs: 278 and 705), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39800.1 (SEQ ID NOs: 279 and 706), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39806.1 (SEQ ID NOs: 280 and 707), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39812.1 (SEQ ID NOs: 281 and 708), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39818.1 (SEQ ID NOs: 282 and 709), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39824.1 (SEQ ID NOs: 283 and 710), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39783.1 (SEQ ID NOs: 284 and 711), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39789.1 (SEQ ID NOs: 285 and 712), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39795.1 (SEQ ID NOs: 286 and 713), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39801.1 (SEQ ID NOs: 287 and 714), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39807.1 (SEQ ID NOs: 288 and 715), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39813.1 (SEQ ID NOs: 289 and 716), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39819.1 (SEQ ID NOs: 290 and 717), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39825.1 (SEQ ID NOs: 291 and 718), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39831.1 (SEQ ID NOs: 292 and 719), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39837.1 (SEQ ID NOs: 293 and 720), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39843.1 (SEQ ID NOs: 294 and 721), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39849.1 (SEQ ID NOs: 295 and 722), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39855.1 (SEQ ID NOs: 296 and 723), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39861.1 (SEQ ID NOs: 297 and 724), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39867.1 (SEQ ID NOs: 298 and 725), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39826.1 (SEQ ID NOs: 299 and 726), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39832.1 (SEQ ID NOs: 300 and 727), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39838.1 (SEQ ID NOs: 301 and 728), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39844.1 (SEQ ID NOs: 302 and 729), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39850.1 (SEQ ID NOs: 303 and 730), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39856.1 (SEQ ID NOs: 304 and 731), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39862.1 (SEQ ID NOs: 305 and 732), ormodified or unmodified variants thereof, wherein the first and/or secondstrand

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39868.1 (SEQ ID NOs: 306 and 733), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39827.1 (SEQ ID NOs: 307 and 734), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39833.1 (SEQ ID NOs: 308 and 735), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39839.1 (SEQ ID NOs: 309 and 736), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39845.1 (SEQ ID NOs: 310 and 737), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39851.1 (SEQ ID NOs: 311 and 738), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39857.1 (SEQ ID NOs: 312 and 739), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39863.1 (SEQ ID NOs: 313 and 740), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39869.1 (SEQ ID NOs: 314 and 741), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39828.1 (SEQ ID NOs: 315 and 742), ormodified or unmodified variants thereof, wherein the first and/or secondstrand

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39834.1 (SEQ ID NOs: 316 and 743), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39840.1 (SEQ ID NOs: 317 and 744), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39846.1 (SEQ ID NOs: 318 and 745), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39852.1 (SEQ ID NOs: 319 and 746), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39858.1 (SEQ ID NOs: 320 and 747), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39864.1 (SEQ ID NOs: 321 and 748), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39870.1 (SEQ ID NOs: 322 and 749), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39829.1 (SEQ ID NOs: 323 and 750), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39835.1 (SEQ ID NOs: 324 and 751), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39841.1 (SEQ ID NOs: 325 and 752), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39853.1 (SEQ ID NOs: 326 and 753), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39859.1 (SEQ ID NOs: 327 and 754), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39865.1 (SEQ ID NOs: 328 and 755), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39871.1 (SEQ ID NOs: 329 and 756), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39830.1 (SEQ ID NOs: 330 and 757), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39836.1 (SEQ ID NOs: 331 and 758), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39842.1 (SEQ ID NOs: 332 and 759), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39848.1 (SEQ ID NOs: 333 and 760), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39854.1 (SEQ ID NOs: 334 and 761), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39860.1 (SEQ ID NOs: 335 and 762), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39866.1 (SEQ ID NOs: 336 and 763), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39992.1 (SEQ ID NOs: 337 and 764), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39998.1 (SEQ ID NOs: 338 and 765), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40004.1 (SEQ ID NOs: 339 and 766), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40010.1 (SEQ ID NOs: 340 and 767), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40016.1 (SEQ ID NOs: 341 and 768), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40022.1 (SEQ ID NOs: 342 and 769), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40028.1 (SEQ ID NOs: 343 and 770), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40034.1 (SEQ ID NOs: 344 and 771), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39999.1 (SEQ ID NOs: 345 and 772), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40005.1 (SEQ ID NOs: 346 and 773), ormodified or unmodified variants thereof, wherein the first and/or secondstrand

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40011.1 (SEQ ID NOs: 347 and 774), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40017.1 (SEQ ID NOs: 348 and 775), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40029.1 (SEQ ID NOs: 349 and 776), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40035.1 (SEQ ID NOs: 350 and 777), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39994.1 (SEQ ID NOs: 351 and 778), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40000.1 (SEQ ID NOs: 352 and 779), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40006.1 (SEQ ID NOs: 353 and 780), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40012.1 (SEQ ID NOs: 354 and 781), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40018.1 (SEQ ID NOs: 355 and 782), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40024.1 (SEQ ID NOs: 356 and 783), ormodified or unmodified variants thereof, wherein the first and/or secondstrand

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40030.1 (SEQ ID NOs: 357 and 784), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40036.1 (SEQ ID NOs: 358 and 785), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39995.1 (SEQ ID NOs: 359 and 786), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40001.1 (SEQ ID NOs: 360 and 787), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40007.1 (SEQ ID NOs: 361 and 788), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40013.1 (SEQ ID NOs: 362 and 789), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40019.1 (SEQ ID NOs: 363 and 790), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40025.1 (SEQ ID NOs: 364 and 791), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40031.1 (SEQ ID NOs: 365 and 792), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40037.1 (SEQ ID NOs: 366 and 793), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39996.1 (SEQ ID NOs: 367 and 794), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40002.1 (SEQ ID NOs: 368 and 795), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40008.1 (SEQ ID NOs: 369 and 796), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40014.1 (SEQ ID NOs: 370 and 797), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40020.1 (SEQ ID NOs: 371 and 798), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40026.1 (SEQ ID NOs: 372 and 799), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40032.1 (SEQ ID NOs: 373 and 800), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40038.1 (SEQ ID NOs: 374 and 801), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39997.1 (SEQ ID NOs: 375 and 802), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40009.1 (SEQ ID NOs: 376 and 803), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40015.1 (SEQ ID NOs: 377 and 804), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40021.1 (SEQ ID NOs: 378 and 805), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40027.1 (SEQ ID NOs: 379 and 806), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40033.1 (SEQ ID NOs: 380 and 807), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40039.1 (SEQ ID NOs: 381 and 808), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40045.1 (SEQ ID NOs: 382 and 809), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40051.1 (SEQ ID NOs: 383 and 810), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40057.1 (SEQ ID NOs: 384 and 811), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40063.1 (SEQ ID NOs: 385 and 812), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40069.1 (SEQ ID NOs: 386 and 813), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40075.1 (SEQ ID NOs: 387 and 814), ormodified or unmodified variants thereof, wherein the first and/or secondstrand

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40081.1 (SEQ ID NOs: 388 and 815), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40040.1 (SEQ ID NOs: 389 and 816), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40046.1 (SEQ ID NOs: 390 and 817), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40052.1 (SEQ ID NOs: 391 and 818), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40058.1 (SEQ ID NOs: 392 and 819), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40064.1 (SEQ ID NOs: 393 and 820), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40070.1 (SEQ ID NOs: 394 and 821), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40076.1 (SEQ ID NOs: 395 and 822), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40082.1 (SEQ ID NOs: 396 and 823), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40041.1 (SEQ ID NOs: 397 and 824), ormodified or unmodified variants thereof, wherein the first and/or secondstrand

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40047.1 (SEQ ID NOs: 398 and 825), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40053.1 (SEQ ID NOs: 399 and 826), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40059.1 (SEQ ID NOs: 400 and 827), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40065.1 (SEQ ID NOs: 401 and 828), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40071.1 (SEQ ID NOs: 402 and 829), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40077.1 (SEQ ID NOs: 403 and 830), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40083.1 (SEQ ID NOs: 404 and 831), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40042.1 (SEQ ID NOs: 405 and 832), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40048.1 (SEQ ID NOs: 406 and 833), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40054.1 (SEQ ID NOs: 407 and 834), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40060.1 (SEQ ID NOs: 408 and 835), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40066.1 (SEQ ID NOs: 409 and 836), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40072.1 (SEQ ID NOs: 410 and 837), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40078.1 (SEQ ID NOs: 411 and 838), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40084.1 (SEQ ID NOs: 412 and 839), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40043.1 (SEQ ID NOs: 413 and 840), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40049.1 (SEQ ID NOs: 414 and 841), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40055.1 (SEQ ID NOs: 415 and 842), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40061.1 (SEQ ID NOs: 416 and 843), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40067.1 (SEQ ID NOs: 417 and 844), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40073.1 (SEQ ID NOs: 418 and 845), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40079.1 (SEQ ID NOs: 419 and 846), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40085.1 (SEQ ID NOs: 420 and 847), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40044.1 (SEQ ID NOs: 421 and 848), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40050.1 (SEQ ID NOs: 422 and 849), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40056.1 (SEQ ID NOs: 423 and 850), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40062.1 (SEQ ID NOs: 424 and 851), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40068.1 (SEQ ID NOs: 425 and 852), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40074.1 (SEQ ID NOs: 426 and 853), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40080.1 (SEQ ID NOs: 427 and 854), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39720.1 (SEQ ID NOs: 1716 and 1754), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39706.1 (SEQ ID NOs: 1717 and 1755), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39712.1 (SEQ ID NOs: 1718 and 1756), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39760.1 (SEQ ID NOs: 1719 and 1757), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39732.1 (SEQ ID NOs: 1720 and 1758), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35541.4 (SEQ ID NOs: 1721 and 1759), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39735.1 or hs_KRAS_(—) 321_A22S26 (SEQ IDNOs: 1722 and 1760), or modified or unmodified variants thereof, whereinthe first and/or second strand further comprise up to about 20additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39741.1, or modified or unmodified variantsthereof, wherein the first and/or second strand further comprise up toabout 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: hs_KRAS_(—)322_A22S26 (SEQ ID NOs: 1723 and1761), or modified or unmodified variants thereof, wherein the firstand/or second strand further comprise up to about 20 additionalnucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39778.1 (SEQ ID NOs: 1724 and 1762), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39790.1 (SEQ ID NOs: 1725 and 1763), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39822.1 (SEQ ID NOs: 1726 and 1764), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35609.4 (SEQ ID NOs: 1727 and 1765), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35581.4 (SEQ ID NOs: 1728 and 1766), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39845.1 (SEQ ID NOs: 1729 and 1767), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39858.1 (SEQ ID NOs: 1730 and 1768), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39870.1 (SEQ ID NOs: 1731 and 1769), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35576.4 (SEQ ID NOs: 1732 and 1770), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35588.4 (SEQ ID NOs: 1733 and 1771), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35600.1 (SEQ ID NOs: 1734 and 1772), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-35606.1 (SEQ ID NOs: 1735 and 1773), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38151.1 (SEQ ID NOs: 1736 and 1774), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38163.1 (SEQ ID NOs: 1737 and 1775), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-39999.1 (SEQ ID NOs: 1738 and 1776), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38159.1 or hs_KRAS_(—) 528_A22S26 (SEQ IDNOs: 1739 and 1777), or modified or unmodified variants thereof, whereinthe first and/or second strand further comprise up to about 20additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38130.1 or hs_KRAS_(—) 531_A22S26 (SEQ IDNOs: 1740 and 1778), or modified or unmodified variants thereof, whereinthe first and/or second strand further comprise up to about 20additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38136.1 (SEQ ID NOs: 1741 and 1779), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40036.1 (SEQ ID NOs: 1742 and 1780), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40008.1 (SEQ ID NOs: 1743 and 1781), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40021.1 (SEQ ID NOs: 1744 and 1782), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40077.1 (SEQ ID NOs: 1745 and 1783), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40072.1 (SEQ ID NOs: 1746 and 1784), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40061.1 (SEQ ID NOs: 1747 and 1785), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-40068.1 (SEQ ID NOs: 1748 and 1786), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38131.1 (SEQ ID NOs: 1749 and 1787), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: AD-38167.1 (SEQ ID NOs: 1750 and 1788), ormodified or unmodified variants thereof, wherein the first and/or secondstrand further comprise up to about 20 additional nucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: hs_KRAS 1273_A22S26 (SEQ ID NOs: 1751 and1789), or modified or unmodified variants thereof, wherein the firstand/or second strand further comprise up to about 20 additionalnucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: hs_KRAS 2892_A37S26 (SEQ ID NOs: 1752 and1790), or modified or unmodified variants thereof, wherein the firstand/or second strand further comprise up to about 20 additionalnucleotides.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand is the sequence of a firstand/or second strand of: hs_KRAS 4731_A22S26 (SEQ ID NOs: 1753 and1791), or modified or unmodified variants thereof, wherein the firstand/or second strand further comprise up to about 20 additionalnucleotides.

In various embodiments, the disclosure comprises a RNAi agent comprisinga sense and an antisense strand, wherein the antisense strand comprisesat least 15 contiguous nucleotides differing by 0, 1, 2, or 3 nt fromthe antisense strand of any RNAi agent disclosed herein, or modified orunmodified variants thereof, wherein the antisense strand optionallyfurther comprises 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more nt (or anyrange thereof, e.g., 0-1, 1-2, 1-3, 1-4 nt, etc.).

In one embodiment, the disclosure comprises any one or more RNAi agentlisted herein.

Specific embodiments wherein the sequences of the first and/or secondstrands are the sequences of the first and/or second strand of a RNAiagent disclosed herein, further comprising up to about 20 additionalnucleotides

In one embodiment, the present disclosure pertains to a compositioncomprising any one or more of: a RNAi agent comprising a first and asecond strand, wherein the sequence of the first and/or second strandcomprise a sequence of 15 contiguous nt from the sequence of a firstand/or second strand of any RNAi agent from any of Tables 1 to 6, ormodified and unmodified variants thereof.

Thus, in various embodiments, the present disclosure pertains to acomposition comprising any one or more of the following:

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35523.3 (SEQ ID NOs: 1 and 428), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35529.1 (SEQ ID NOs: 2 and 429), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35535.4 (SEQ ID NOs: 3 and 430), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35541.4 (SEQ ID NOs: 4 and 431), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35547.4 (SEQ ID NOs: 5 and 432), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35553.4 (SEQ ID NOs: 6 and 433), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35559.4 (SEQ ID NOs: 7 and 434), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35565.4 (SEQ ID NOs: 8 and 435), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35524.4 (SEQ ID NOs: 9 and 436), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35530.4 (SEQ ID NOs: 10 and 437), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35536.4 (SEQ ID NOs: 11 and 438), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35542.4 (SEQ ID NOs: 12 and 439), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35548.4 (SEQ ID NOs: 13 and 440), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35554.4 (SEQ ID NOs: 14 and 441), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35560.2 (SEQ ID NOs: 15 and 442), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35566.4 (SEQ ID NOs: 16 and 443), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35525.2 (SEQ ID NOs: 17 and 444), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first second strand of: AD-35531.4 (SEQ ID NOs: 18 and445), or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35537.4 (SEQ ID NOs: 19 and 446), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35543.2 (SEQ ID NOs: 20 and 447), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35549.4 (SEQ ID NOs: 21 and 448), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35555.4 (SEQ ID NOs: 22 and 449), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35561.4 (SEQ ID NOs: 23 and 450), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35567.4 (SEQ ID NOs: 24 and 451), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35526.4 (SEQ ID NOs: 25 and 452), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35532.4 (SEQ ID NOs: 26 and 453), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35538.4 (SEQ ID NOs: 27 and 454), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35544.4 (SEQ ID NOs: 28 and 455), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35550.4 (SEQ ID NOs: 29 and 456), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35556.4 (SEQ ID NOs: 30 and 457), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35562.4 (SEQ ID NOs: 31 and 458), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35568.4 (SEQ ID NOs: 32 and 459), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35527.4 (SEQ ID NOs: 33 and 460), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35533.4 (SEQ ID NOs: 34 and 461), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35539.4 (SEQ ID NOs: 35 and 462), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35545.4 (SEQ ID NOs: 36 and 463), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35551.4 (SEQ ID NOs: 37 and 464), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35563.4 (SEQ ID NOs: 38 and 465), or a modified or unmodified variant

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35528.4 (SEQ ID NOs: 39 and 466), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35540.4 (SEQ ID NOs: 40 and 467), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35546.4 (SEQ ID NOs: 41 and 468), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35552.4 (SEQ ID NOs: 42 and 469), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35558.4 (SEQ ID NOs: 43 and 470), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35564.4 (SEQ ID NOs: 44 and 471), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35570.4 (SEQ ID NOs: 45 and 472), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35571.4 (SEQ ID NOs: 46 and 473), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35577.4 (SEQ ID NOs: 47 and 474), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35583.4 (SEQ ID NOs: 48 and 475), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35589.4 (SEQ ID NOs: 49 and 476), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35595.4 (SEQ ID NOs: 50 and 477), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35601.4 (SEQ ID NOs: 51 and 478), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35607.4 (SEQ ID NOs: 52 and 479), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35613.4 (SEQ ID NOs: 53 and 480), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35572.4 (SEQ ID NOs: 54 and 481), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35578.4 (SEQ ID NOs: 55 and 482), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35584.4 (SEQ ID NOs: 56 and 483), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35590.4 (SEQ ID NOs: 57 and 484), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35596.4 (SEQ ID NOs: 58 and 485), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first second strand of: AD-35602.4 (SEQ ID NOs: 59 and486), or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35608.4 (SEQ ID NOs: 60 and 487), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35614.4 (SEQ ID NOs: 61 and 488), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35573.4 (SEQ ID NOs: 62 and 489), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35579.4 (SEQ ID NOs: 63 and 490), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35585.4 (SEQ ID NOs: 64 and 491), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35591.4 (SEQ ID NOs: 65 and 492), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35597.4 (SEQ ID NOs: 66 and 493), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35603.4 (SEQ ID NOs: 67 and 494), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35609.4 (SEQ ID NOs: 68 and 495), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35615.4 (SEQ ID NOs: 69 and 496), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35574.4 (SEQ ID NOs: 70 and 497), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35580.1 (SEQ ID NOs: 71 and 498), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35586.4 (SEQ ID NOs: 72 and 499), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35592.4 (SEQ ID NOs: 73 and 500), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35598.4 (SEQ ID NOs: 74 and 501), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35604.4 (SEQ ID NOs: 75 and 502), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35610.4 (SEQ ID NOs: 76 and 503), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35616.4 (SEQ ID NOs: 77 and 504), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35575.4 (SEQ ID NOs: 78 and 505), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35581.4 (SEQ ID NOs: 79 and 506), or a modified or unmodified variant

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35587.4 (SEQ ID NOs: 80 and 507), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35593.4 (SEQ ID NOs: 81 and 508), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35599.4 (SEQ ID NOs: 82 and 509), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35605.4 (SEQ ID NOs: 83 and 510), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35611.4 (SEQ ID NOs: 84 and 511), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35617.4 (SEQ ID NOs: 85 and 512), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35576.4 (SEQ ID NOs: 86 and 513), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35588.4 (SEQ ID NOs: 87 and 514), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35667.1 (SEQ ID NOs: 88 and 515), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35673.1 (SEQ ID NOs: 89 and 516), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35679.1 (SEQ ID NOs: 90 and 517), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35685.1 (SEQ ID NOs: 91 and 518), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35691.1 (SEQ ID NOs: 92 and 519), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35557.1 (SEQ ID NOs: 93 and 520), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35618.1 (SEQ ID NOs: 94 and 521), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35569.1 (SEQ ID NOs: 95 and 522), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35534.1 (SEQ ID NOs: 96 and 523), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35582.1 (SEQ ID NOs: 97 and 524), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35594.1 (SEQ ID NOs: 98 and 525), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35600.1 (SEQ ID NOs: 99 and 526), or a modified or unmodified variantthereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first second strand of: AD-35606.1 (SEQ ID NOs: 100 and527), or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35612.1 (SEQ ID NOs: 101 and 528), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38127.1 (SEQ ID NOs: 102 and 529), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38133.1 (SEQ ID NOs: 103 and 530), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38139.1 (SEQ ID NOs: 104 and 531), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38145.1 (SEQ ID NOs: 105 and 532), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38151.1 (SEQ ID NOs: 106 and 533), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38157.1 (SEQ ID NOs: 107 and 534), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38163.1 (SEQ ID NOs: 108 and 535), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38169.1 (SEQ ID NOs: 109 and 536), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38128.1 (SEQ ID NOs: 110 and 537), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38134.1 (SEQ ID NOs: 111 and 538), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38140.1 (SEQ ID NOs: 112 and 539), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38146.1 (SEQ ID NOs: 113 and 540), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38152.1 (SEQ ID NOs: 114 and 541), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38158.1 (SEQ ID NOs: 115 and 542), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38164.1 (SEQ ID NOs: 116 and 543), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38170.1 (SEQ ID NOs: 117 and 544), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38129.1 (SEQ ID NOs: 118 and 545), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38135.1 (SEQ ID NOs: 119 and 546), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38141.1 (SEQ ID NOs: 120 and 547), or a modified or unmodifiedvariant

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38147.1 (SEQ ID NOs: 121 and 548), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38153.1 (SEQ ID NOs: 122 and 549), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38159.1 (SEQ ID NOs: 123 and 550), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38165.1 (SEQ ID NOs: 124 and 551), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38171.1 (SEQ ID NOs: 125 and 552), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38130.1 (SEQ ID NOs: 126 and 553), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38136.1 (SEQ ID NOs: 127 and 554), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38142.1 (SEQ ID NOs: 128 and 555), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38148.1 (SEQ ID NOs: 129 and 556), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38154.1 (SEQ ID NOs: 130 and 557), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38160.1 (SEQ ID NOs: 131 and 558), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38166.1 (SEQ ID NOs: 132 and 559), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38172.1 (SEQ ID NOs: 133 and 560), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38131.1 (SEQ ID NOs: 134 and 561), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38137.1 (SEQ ID NOs: 135 and 562), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38143.1 (SEQ ID NOs: 136 and 563), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38149.1 (SEQ ID NOs: 137 and 564), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38155.1 (SEQ ID NOs: 138 and 565), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38161.1 (SEQ ID NOs: 139 and 566), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38167.1 (SEQ ID NOs: 140 and 567), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first second strand of: AD-38173.1 (SEQ ID NOs: 141 and568), or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38132.1 (SEQ ID NOs: 142 and 569), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38138.1 (SEQ ID NOs: 143 and 570), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38144.1 (SEQ ID NOs: 144 and 571), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38150.1 (SEQ ID NOs: 145 and 572), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38156.1 (SEQ ID NOs: 146 and 573), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38162.1 (SEQ ID NOs: 147 and 574), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38168.1 (SEQ ID NOs: 148 and 575), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38174.1 (SEQ ID NOs: 149 and 576), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39683.1 (SEQ ID NOs: 150 and 577), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39689.1 (SEQ ID NOs: 151 and 578), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39695.1 (SEQ ID NOs: 152 and 579), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39701.1 (SEQ ID NOs: 153 and 580), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39707.1 (SEQ ID NOs: 154 and 581), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39713.1 (SEQ ID NOs: 155 and 582), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39719.1 (SEQ ID NOs: 156 and 583), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39725.1 (SEQ ID NOs: 157 and 584), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39684.1 (SEQ ID NOs: 158 and 585), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39690.1 (SEQ ID NOs: 159 and 586), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39696.1 (SEQ ID NOs: 160 and 587), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39702.1 (SEQ ID NOs: 161 and 588), or a modified or unmodifiedvariant

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39708.1 (SEQ ID NOs: 162 and 589), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39714.1 (SEQ ID NOs: 163 and 590), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39720.1 (SEQ ID NOs: 164 and 591), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39726.1 (SEQ ID NOs: 165 and 592), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39685.1 (SEQ ID NOs: 166 and 593), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39691.1 (SEQ ID NOs: 167 and 594), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39697.1 (SEQ ID NOs: 168 and 595), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39703.1 (SEQ ID NOs: 169 and 596), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39709.1 (SEQ ID NOs: 170 and 597), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39715.1 (SEQ ID NOs: 171 and 598), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39721.1 (SEQ ID NOs: 172 and 599), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39727.1 (SEQ ID NOs: 173 and 600), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39686.1 (SEQ ID NOs: 174 and 601), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39692.1 (SEQ ID NOs: 175 and 602), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39698.1 (SEQ ID NOs: 176 and 603), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39704.1 (SEQ ID NOs: 177 and 604), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39710.1 (SEQ ID NOs: 178 and 605), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39716.1 (SEQ ID NOs: 179 and 606), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39722.1 (SEQ ID NOs: 180 and 607), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39728.1 (SEQ ID NOs: 181 and 608), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first second strand of: AD-39687.1 (SEQ ID NOs: 182 and609), or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39693.1 (SEQ ID NOs: 183 and 610), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39699.1 (SEQ ID NOs: 184 and 611), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39705.1 (SEQ ID NOs: 185 and 612), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39711.1 (SEQ ID NOs: 186 and 613), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39717.1 (SEQ ID NOs: 187 and 614), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39723.1 (SEQ ID NOs: 188 and 615), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39729.1 (SEQ ID NOs: 189 and 616), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39688.1 (SEQ ID NOs: 190 and 617), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39694.1 (SEQ ID NOs: 191 and 618), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39700.1 (SEQ ID NOs: 192 and 619), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39706.1 (SEQ ID NOs: 193 and 620), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39712.1 (SEQ ID NOs: 194 and 621), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39718.1 (SEQ ID NOs: 195 and 622), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39724.1 (SEQ ID NOs: 196 and 623), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39730.1 (SEQ ID NOs: 197 and 624), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39736.1 (SEQ ID NOs: 198 and 625), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39742.1 (SEQ ID NOs: 199 and 626), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39748.1 (SEQ ID NOs: 200 and 627), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39754.1 (SEQ ID NOs: 201 and 628), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39760.1 (SEQ ID NOs: 202 and 629), or a modified or unmodifiedvariant

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39766.1 (SEQ ID NOs: 203 and 630), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39772.1 (SEQ ID NOs: 204 and 631), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39731.1 (SEQ ID NOs: 205 and 632), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39737.1 (SEQ ID NOs: 206 and 633), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39743.1 (SEQ ID NOs: 207 and 634), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39749.1 (SEQ ID NOs: 208 and 635), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39755.1 (SEQ ID NOs: 209 and 636), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39761.1 (SEQ ID NOs: 210 and 637), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39767.1 (SEQ ID NOs: 211 and 638), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39773.1 (SEQ ID NOs: 212 and 639), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39732.1 (SEQ ID NOs: 213 and 640), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39738.1 (SEQ ID NOs: 214 and 641), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39744.1 (SEQ ID NOs: 215 and 642), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39750.1 (SEQ ID NOs: 216 and 643), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39756.1 (SEQ ID NOs: 217 and 644), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39762.1 (SEQ ID NOs: 218 and 645), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39768.1 (SEQ ID NOs: 219 and 646), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39774.1 (SEQ ID NOs: 220 and 647), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39733.1 (SEQ ID NOs: 221 and 648), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39739.1 (SEQ ID NOs: 222 and 649), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first second strand of: AD-39745.1 (SEQ ID NOs: 223 and650), or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39751.1 (SEQ ID NOs: 224 and 651), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39757.1 (SEQ ID NOs: 225 and 652), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39763.1 (SEQ ID NOs: 226 and 653), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39769.1 (SEQ ID NOs: 227 and 654), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39775.1 (SEQ ID NOs: 228 and 655), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39734.1 (SEQ ID NOs: 229 and 656), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39740.1 (SEQ ID NOs: 230 and 657), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39746.1 (SEQ ID NOs: 231 and 658), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39752.1 (SEQ ID NOs: 232 and 659), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39758.1 (SEQ ID NOs: 233 and 660), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39764.1 (SEQ ID NOs: 234 and 661), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39770.1 (SEQ ID NOs: 235 and 662), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39776.1 (SEQ ID NOs: 236 and 663), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39735.1 (SEQ ID NOs: 237 and 664), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39741.1 (SEQ ID NOs: 238 and 665), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39747.1 (SEQ ID NOs: 239 and 666), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39753.1 (SEQ ID NOs: 240 and 667), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39759.1 (SEQ ID NOs: 241 and 668), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39765.1 (SEQ ID NOs: 242 and 669), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39771.1 (SEQ ID NOs: 243 and 670), or a modified or unmodifiedvariant

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39778.1 (SEQ ID NOs: 244 and 671), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39784.1 (SEQ ID NOs: 245 and 672), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39790.1 (SEQ ID NOs: 246 and 673), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39796.1 (SEQ ID NOs: 247 and 674), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39802.1 (SEQ ID NOs: 248 and 675), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39808.1 (SEQ ID NOs: 249 and 676), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39814.1 (SEQ ID NOs: 250 and 677), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39820.1 (SEQ ID NOs: 251 and 678), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39779.1 (SEQ ID NOs: 252 and 679), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39785.1 (SEQ ID NOs: 253 and 680), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39791.1 (SEQ ID NOs: 254 and 681), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39797.1 (SEQ ID NOs: 255 and 682), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39803.1 (SEQ ID NOs: 256 and 683), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39809.1 (SEQ ID NOs: 257 and 684), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39815.1 (SEQ ID NOs: 258 and 685), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39821.1 (SEQ ID NOs: 259 and 686), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39780.1 (SEQ ID NOs: 260 and 687), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39786.1 (SEQ ID NOs: 261 and 688), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39792.1 (SEQ ID NOs: 262 and 689), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39798.1 (SEQ ID NOs: 263 and 690), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first second strand of: AD-39804.1 (SEQ ID NOs: 264 and691), or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39810.1 (SEQ ID NOs: 265 and 692), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39816.1 (SEQ ID NOs: 266 and 693), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39822.1 (SEQ ID NOs: 267 and 694), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39781.1 (SEQ ID NOs: 268 and 695), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39787.1 (SEQ ID NOs: 269 and 696), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39793.1 (SEQ ID NOs: 270 and 697), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39799.1 (SEQ ID NOs: 271 and 698), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39805.1 (SEQ ID NOs: 272 and 699), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39811.1 (SEQ ID NOs: 273 and 700), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39817.1 (SEQ ID NOs: 274 and 701), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39823.1 (SEQ ID NOs: 275 and 702), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39782.1 (SEQ ID NOs: 276 and 703), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39788.1 (SEQ ID NOs: 277 and 704), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39794.1 (SEQ ID NOs: 278 and 705), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39800.1 (SEQ ID NOs: 279 and 706), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39806.1 (SEQ ID NOs: 280 and 707), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39812.1 (SEQ ID NOs: 281 and 708), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39818.1 (SEQ ID NOs: 282 and 709), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39824.1 (SEQ ID NOs: 283 and 710), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39783.1 (SEQ ID NOs: 284 and 711), or a modified or unmodifiedvariant

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39789.1 (SEQ ID NOs: 285 and 712), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39795.1 (SEQ ID NOs: 286 and 713), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39801.1 (SEQ ID NOs: 287 and 714), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39807.1 (SEQ ID NOs: 288 and 715), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39813.1 (SEQ ID NOs: 289 and 716), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39819.1 (SEQ ID NOs: 290 and 717), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39825.1 (SEQ ID NOs: 291 and 718), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39831.1 (SEQ ID NOs: 292 and 719), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39837.1 (SEQ ID NOs: 293 and 720), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39843.1 (SEQ ID NOs: 294 and 721), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39849.1 (SEQ ID NOs: 295 and 722), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39855.1 (SEQ ID NOs: 296 and 723), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39861.1 (SEQ ID NOs: 297 and 724), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39867.1 (SEQ ID NOs: 298 and 725), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39826.1 (SEQ ID NOs: 299 and 726), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39832.1 (SEQ ID NOs: 300 and 727), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39838.1 (SEQ ID NOs: 301 and 728), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39844.1 (SEQ ID NOs: 302 and 729), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39850.1 (SEQ ID NOs: 303 and 730), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39856.1 (SEQ ID NOs: 304 and 731), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first second strand of: AD-39862.1 (SEQ ID NOs: 305 and732), or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39868.1 (SEQ ID NOs: 306 and 733), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39827.1 (SEQ ID NOs: 307 and 734), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39833.1 (SEQ ID NOs: 308 and 735), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39839.1 (SEQ ID NOs: 309 and 736), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39845.1 (SEQ ID NOs: 310 and 737), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39851.1 (SEQ ID NOs: 311 and 738), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39857.1 (SEQ ID NOs: 312 and 739), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39863.1 (SEQ ID NOs: 313 and 740), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39869.1 (SEQ ID NOs: 314 and 741), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39828.1 (SEQ ID NOs: 315 and 742), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39834.1 (SEQ ID NOs: 316 and 743), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39840.1 (SEQ ID NOs: 317 and 744), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39846.1 (SEQ ID NOs: 318 and 745), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39852.1 (SEQ ID NOs: 319 and 746), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39858.1 (SEQ ID NOs: 320 and 747), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39864.1 (SEQ ID NOs: 321 and 748), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39870.1 (SEQ ID NOs: 322 and 749), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39829.1 (SEQ ID NOs: 323 and 750), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39835.1 (SEQ ID NOs: 324 and 751), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39841.1 (SEQ ID NOs: 325 and 752), or a modified or unmodifiedvariant

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39853.1 (SEQ ID NOs: 326 and 753), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39859.1 (SEQ ID NOs: 327 and 754), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39865.1 (SEQ ID NOs: 328 and 755), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39871.1 (SEQ ID NOs: 329 and 756), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39830.1 (SEQ ID NOs: 330 and 757), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39836.1 (SEQ ID NOs: 331 and 758), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39842.1 (SEQ ID NOs: 332 and 759), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39848.1 (SEQ ID NOs: 333 and 760), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39854.1 (SEQ ID NOs: 334 and 761), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39860.1 (SEQ ID NOs: 335 and 762), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39866.1 (SEQ ID NOs: 336 and 763), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39992.1 (SEQ ID NOs: 337 and 764), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39998.1 (SEQ ID NOs: 338 and 765), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40004.1 (SEQ ID NOs: 339 and 766), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40010.1 (SEQ ID NOs: 340 and 767), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40016.1 (SEQ ID NOs: 341 and 768), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40022.1 (SEQ ID NOs: 342 and 769), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40028.1 (SEQ ID NOs: 343 and 770), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40034.1 (SEQ ID NOs: 344 and 771), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39999.1 (SEQ ID NOs: 345 and 772), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first second strand of: AD-40005.1 (SEQ ID NOs: 346 and773), or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40011.1 (SEQ ID NOs: 347 and 774), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40017.1 (SEQ ID NOs: 348 and 775), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40029.1 (SEQ ID NOs: 349 and 776), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40035.1 (SEQ ID NOs: 350 and 777), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39994.1 (SEQ ID NOs: 351 and 778), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40000.1 (SEQ ID NOs: 352 and 779), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40006.1 (SEQ ID NOs: 353 and 780), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40012.1 (SEQ ID NOs: 354 and 781), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40018.1 (SEQ ID NOs: 355 and 782), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40024.1 (SEQ ID NOs: 356 and 783), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40030.1 (SEQ ID NOs: 357 and 784), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40036.1 (SEQ ID NOs: 358 and 785), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39995.1 (SEQ ID NOs: 359 and 786), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40001.1 (SEQ ID NOs: 360 and 787), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40007.1 (SEQ ID NOs: 361 and 788), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40013.1 (SEQ ID NOs: 362 and 789), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40019.1 (SEQ ID NOs: 363 and 790), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40025.1 (SEQ ID NOs: 364 and 791), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40031.1 (SEQ ID NOs: 365 and 792), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40037.1 (SEQ ID NOs: 366 and 793), or a modified or unmodifiedvariant

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39996.1 (SEQ ID NOs: 367 and 794), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40002.1 (SEQ ID NOs: 368 and 795), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40008.1 (SEQ ID NOs: 369 and 796), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40014.1 (SEQ ID NOs: 370 and 797), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40020.1 (SEQ ID NOs: 371 and 798), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40026.1 (SEQ ID NOs: 372 and 799), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40032.1 (SEQ ID NOs: 373 and 800), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40038.1 (SEQ ID NOs: 374 and 801), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39997.1 (SEQ ID NOs: 375 and 802), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40009.1 (SEQ ID NOs: 376 and 803), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40015.1 (SEQ ID NOs: 377 and 804), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40021.1 (SEQ ID NOs: 378 and 805), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40027.1 (SEQ ID NOs: 379 and 806), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40033.1 (SEQ ID NOs: 380 and 807), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40039.1 (SEQ ID NOs: 381 and 808), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40045.1 (SEQ ID NOs: 382 and 809), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40051.1 (SEQ ID NOs: 383 and 810), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40057.1 (SEQ ID NOs: 384 and 811), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40063.1 (SEQ ID NOs: 385 and 812), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40069.1 (SEQ ID NOs: 386 and 813), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first second strand of: AD-40075.1 (SEQ ID NOs: 387 and814), or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40081.1 (SEQ ID NOs: 388 and 815), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40040.1 (SEQ ID NOs: 389 and 816), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40046.1 (SEQ ID NOs: 390 and 817), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40052.1 (SEQ ID NOs: 391 and 818), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40058.1 (SEQ ID NOs: 392 and 819), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40064.1 (SEQ ID NOs: 393 and 820), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40070.1 (SEQ ID NOs: 394 and 821), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40076.1 (SEQ ID NOs: 395 and 822), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40082.1 (SEQ ID NOs: 396 and 823), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40041.1 (SEQ ID NOs: 397 and 824), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40047.1 (SEQ ID NOs: 398 and 825), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40053.1 (SEQ ID NOs: 399 and 826), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40059.1 (SEQ ID NOs: 400 and 827), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40065.1 (SEQ ID NOs: 401 and 828), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40071.1 (SEQ ID NOs: 402 and 829), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40077.1 (SEQ ID NOs: 403 and 830), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40083.1 (SEQ ID NOs: 404 and 831), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40042.1 (SEQ ID NOs: 405 and 832), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40048.1 (SEQ ID NOs: 406 and 833), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40054.1 (SEQ ID NOs: 407 and 834), or a modified or unmodifiedvariant

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40060.1 (SEQ ID NOs: 408 and 835), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40066.1 (SEQ ID NOs: 409 and 836), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40072.1 (SEQ ID NOs: 410 and 837), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40078.1 (SEQ ID NOs: 411 and 838), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40084.1 (SEQ ID NOs: 412 and 839), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40043.1 (SEQ ID NOs: 413 and 840), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40049.1 (SEQ ID NOs: 414 and 841), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40055.1 (SEQ ID NOs: 415 and 842), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40061.1 (SEQ ID NOs: 416 and 843), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40067.1 (SEQ ID NOs: 417 and 844), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40073.1 (SEQ ID NOs: 418 and 845), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40079.1 (SEQ ID NOs: 419 and 846), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40085.1 (SEQ ID NOs: 420 and 847), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40044.1 (SEQ ID NOs: 421 and 848), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40050.1 (SEQ ID NOs: 422 and 849), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40056.1 (SEQ ID NOs: 423 and 850), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40062.1 (SEQ ID NOs: 424 and 851), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40068.1 (SEQ ID NOs: 425 and 852), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40074.1 (SEQ ID NOs: 426 and 853), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40080.1 (SEQ ID NOs: 427 and 854), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39720.1 (SEQ ID NOs: 1716 and 1754), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39706.1 (SEQ ID NOs: 1717 and 1755), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39712.1 (SEQ ID NOs: 1718 and 1756), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39760.1 (SEQ ID NOs: 1719 and 1757), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39732.1 (SEQ ID NOs: 1720 and 1758), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35541.4 (SEQ ID NOs: 1721 and 1759), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39735.1 or hs_KRAS_(—)321_A22S26 (SEQ ID NOs: 1722 and 1760), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39741.1, or a modified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:hs_KRAS_(—)322_A22S26 (SEQ ID NOs: 1723 and 1761), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39778.1 (SEQ ID NOs: 1724 and 1762), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39790.1 (SEQ ID NOs: 1725 and 1763), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39822.1 (SEQ ID NOs: 1726 and 1764), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35609.4 (SEQ ID NOs: 1727 and 1765), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35581.4 (SEQ ID NOs: 1728 and 1766), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39845.1 (SEQ ID NOs: 1729 and 1767), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39858.1 (SEQ ID NOs: 1730 and 1768), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39870.1 (SEQ ID NOs: 1731 and 1769), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35576.4 (SEQ ID NOs: 1732 and 1770), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35588.4 (SEQ ID NOs: 1733 and 1771), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35600.1 (SEQ ID NOs: 1734 and 1772), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-35606.1 (SEQ ID NOs: 1735 and 1773), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38151.1 (SEQ ID NOs: 1736 and 1774), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38163.1 (SEQ ID NOs: 1737 and 1775), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-39999.1 (SEQ ID NOs: 1738 and 1776), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38159.1 or hs_KRAS_(—)528_A22S26 (SEQ ID NOs: 1739 and 1777), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38130.1 or hs_KRAS_(—)531_A22S26 (SEQ ID NOs: 1740 and 1778), or amodified or unmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38136.1 (SEQ ID NOs: 1741 and 1779), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40036.1 (SEQ ID NOs: 1742 and 1780), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40008.1 (SEQ ID NOs: 1743 and 1781), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40021.1 (SEQ ID NOs: 1744 and 1782), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40077.1 (SEQ ID NOs: 1745 and 1783), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40072.1 (SEQ ID NOs: 1746 and 1784), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40061.1 (SEQ ID NOs: 1747 and 1785), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-40068.1 (SEQ ID NOs: 1748 and 1786), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38131.1 (SEQ ID NOs: 1749 and 1787), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:AD-38167.1 (SEQ ID NOs: 1750 and 1788), or a modified or unmodifiedvariant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:hs_KRAS 1273_A22S26 (SEQ ID NOs: 1751 and 1789), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:hs_KRAS 2892_A37S26 (SEQ ID NOs: 1752 and 1790), or a modified orunmodified variant thereof.

A RNAi agent comprising a first and a second strand, wherein thesequence of the first and/or second strand comprise a sequence of 15contiguous nt from the sequence of a first and/or second strand of:hs_KRAS 4731_A22S26 (SEQ ID NOs: 1753 and 1791), or a modified orunmodified variant thereof.

In various embodiments, the disclosure comprises a RNAi agent comprisinga sense and an antisense strand, wherein the antisense strand comprisesat least 15 contiguous nucleotides differing by 0, 1, 2, or 3 nt fromthe antisense strand of any RNAi agent disclosed herein, or a modifiedor unmodified variant thereof, wherein the antisense strand optionallyfurther comprises 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more nt (or anyrange thereof, e.g., 0-1, 1-2, 1-3, 1-4 nt, etc.).

In one embodiment, the disclosure comprises any one or more RNAi agentlisted herein.

Overlapping sets of RNAi agents to KRAS

In various embodiments, the present disclosure relates to groups of RNAiagents to KRAS with overlapping sequences. Thus, the present disclosureencompasses groups of RNAi agents wherein each RNAi agent in the groupoverlaps with each other RNAi agent in the same group by at least 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or more nucleotides.Particularly, in one embodiment, the overlap is at least 12 nt.

Some of the RNAi agents listed herein overlap each other in sequence.Table 2 presents a compilation of some of these groups of overlappingRNAi agents, wherein each member of a group overlaps with each othermember of the same group by at least 12 nt. A 12-nt portion of theoverlap of the sense and anti-sense strand are presented.

Thus, for example, as shown in Table 4, the sequences of duplexesAD-39695.1, AD-39689.1,AD-39707.1, AD-39683.1, and AD-39701.1 alloverlap, wherein the overlap in sense strand comprises the sequenceCUGAAUAUAAAC (SEQ ID NO: 1874) and the overlap in the anti-sense strandcomprises the sequence GUUUAUAUUCAG (SEQ ID NO: 1875).

However, in the present disclosure encompasses any set or subset orgroup or subgroup of KRAS RNAi agents which share the common technicalfeature of a sequence overlap (e.g., by at least 12 nt). Thus thepresent disclosure also encompasses the example groups of AD-39695.1,AD-39689.1, AD-39707.1, AD-39683.1, and AD-39701.1, but also thesesubgroups: AD-39695.1 and AD-39689.1; AD-39695.1 and AD-39707.1;AD-39695.1, AD-39689.1, and AD-39701.1; AD-39689.1, AD-39707.1, andAD-39701.1; AD-39707.1 and AD-39683.1; AD-39707.1, AD-39683.1, andAD-39701.1; etc, and any other group of overlapping KRAS RNAi agents.

Thus, these and other various sets of overlapping RNAi agents presentedin Table 4 share common technical features, for example, the overlap inthe sense and anti-sense strand.

Particular sets of overlapping RNAi agents to KRAS are provided below inTable 4.

The present disclosure thus encompasses any group or subgroup of RNAiagents comprising a common technical feature, wherein the commontechnical feature is an overlap (e.g., of at least 12 nt) of a sequencein the sense or anti-sense strand.

Thus:

The present disclosure encompasses a RNAi agent comprising a first and asecond strand, wherein the first strand comprises at least 15 contiguousnucleotides differing by 0, 1, 2, or 3 nt from the first strand of,and/or the second strand comprises at least 15 contiguous nucleotidesdiffering by 0, 1, 2, or 3 nt from the second strand, of any of thegroup or subgroup or set or subset of overlapping RNAi agents presentedin Table 4.

The present disclosure similarly encompasses various embodimentsencompassing groups of overlapping RNAi agents presented in Table 4.

Additional Definitions

Unless defined otherwise, the technical and scientific terms used hereinhave the same meaning as that usually understood by a specialistfamiliar with the field to which the present disclosure belongs.

Unless indicated otherwise, all methods, steps, techniques andmanipulations that are not specifically described in detail can beperformed and have been performed in a manner known per se, as will beclear to the skilled person. Reference is for example again made to thestandard handbooks and the general background art mentioned herein andto the further references cited therein.

Claims to the present disclosure are non-limiting and are providedbelow.

Although particular embodiments and claims have been disclosed herein indetail, this has been done by way of example for purposes ofillustration only, and is not intended to be limiting with respect tothe scope of the appended claims, or the scope of subject matter ofclaims of any corresponding future application. In particular, it iscontemplated by the inventors that various substitutions, alterations,and modifications may be made to the present disclosure withoutdeparting from the spirit and scope of the present disclosure as definedby the claims. The choice of nucleic acid starting material, clone ofinterest, or library type is believed to be a matter of routine for aperson of ordinary skill in the art with knowledge of the embodimentsdescribed herein. Other aspects, advantages, and modificationsconsidered to be within the scope of the following claims. Redrafting ofclaim scope in later-filed corresponding applications may be due tolimitations by the patent laws of various countries and should not beinterpreted as giving up subject matter of the claims.

Various additional formulations and obvious variants of the describedRNAi agents to KRAS can be devised by those of ordinary skill in theart. Non-limiting example RNAi agents to KRAS are described in theExamples below, which do not limit the scope of the present disclosureas described in the claims.

EXAMPLES Example 1 Bioinformatics and KRAS RNAi Agent (siRNA) Sequences

The sequences of unmodifed and example modified KRAS RNAi agentsequences are provided in Tables 2 and 3, below.

KRAS oligonucleotide design is carried out to identify siRNAs targetingmRNAs encoding the KRAS gene.

Experimental Methods

Bioinformatics

Transcripts

siRNA design is carried out to identify RNAi agents (e.g., siRNAs)targeting the human Kirsten rat sarcoma viral oncogene (KRAS). Designuses the following transcripts from the NCBI RefSeq collection:KRAS—NM_(—)033360.2, NM_(—)004985.3. For KRAS, the requirement ofperfect matching to the non-human primate Macaca fascicularis is waived.

siRNA Design and Specificity Prediction

The predicted specificity of all possible 19mers is predicted from eachsequence. Candidate 19mers are then selected as matching Coding Sequence(“CDS”) or Untranslated Regions (“UTRs”). The candidate siRNAs for eachgene (KRAS, 432 from CDS) are used in a comprehensive search against thehuman transcriptome (defined as the set of NM_(—) and XM_(—) recordswithin the human NCBI Refseq set) using the FASTA algorithm. The perlscript ‘parseFasta.pl’ is then used to parse the alignments and generatea score based on the position and number of mismatches between the siRNAand any potential ‘off-target’ transcript. The off-target score isweighted to emphasize differences in the ‘seed’ region of siRNAs, inpositions 2-9 from the 5′ end of the molecule. Each oligo-transcriptpair from the FASTA search is given a mismatch score by summing theindividual mismatch scores; mismatches in the position 2-9 are countedas 2.8, mismatches in the cleavage site positions 10-11 are counted as1.2, and mismatches in region 12-19 counted as 1.0. An additionaloff-target prediction is carried out by comparing the frequency ofheptamers and octomers derived from 3 distinct, seed-derived hexamers ofeach oligo. The hexamers from positions 2-7 relative to the 5′ start isused to create 2 heptamers and one octomer. We create ‘heptamer1’ byadding a 3′ A to the hexamer; we create heptamer2 bp adding a 5′ A tothe hexamer; we create the octomer by adding an A to both 5′ and 3′ endsof the hexamer. The frequency of octomers and heptamers in the human3′UTRome (defined as the subsequence of the transcriptome from NCBI'sRefseq database where the end of the coding region, the ‘CDS’, isclearly defined) is pre-calculated. The octomer frequency is normalizedto the heptamer frequency using the median value from the range ofoctomer frequencies. A ‘mirSeedScore’ is then calculated by calculatingthe sum of [(3×normalized octomer count)+(2×heptamer2count)+(1×heptamer1 count)].

Both siRNAs strands are assigned to a category of specificity accordingto the calculated scores: a score above 3 qualifies as highly specific,equal to 3 as specific and between 2.2 and 2.8 as moderately specific.We sorted by the specificity of the antisense strand.

siRNA Sequence Selection

Sense and antisense derived siRNA oligos are synthesized and formed intoduplexes. The total numbers of duplexes per gene were: KRAS, 432.

Synthesis of KRAS Sequences

Synthesis:

KRAS sequences are synthesized on MerMade 192 synthesizer at 1 μmolscale. A total of 864 single strands (432 duplexes) for KRAS aresynthesized for the human KRAS gene. For all the sequences, ‘endolight’chemistry is applied as detailed below.

-   -   All pyrimidines (cytosine and uridine) in the sense strand are        replaced with corresponding 2′-O-Methyl bases (2′ 0-Methyl C and        2′-O-Methyl U)    -   In the antisense strand, pyrimidines (C and U) adjacent to        (towards 5′ position) ribo A nucleoside are replaced with their        corresponding 2-O-Methyl nucleosides    -   A two base dTdT extension at 3′ end of both sense and anti sense        sequences is introduced. This two base overhang has a        phosphodiester linkage    -   The sequence file is converted to a text file to make it        compatible for loading in the MerMade 192 synthesis software    -   A unique ID is generated for each single strand and these are        shown in Tables 1 to 3.

The synthesis of KRAS sequences used solid supported oligonucleotidesynthesis using phosphoramidite chemistry

The synthesis of the above sequences is performed at 1 μm scale in 96well plates and 192 sequences are made per run. The amidite solutionsare prepared at 0.1M concentration and ethyl thio tetrazole (0.6M inAcetonitrile) is used as activator.

Cleavage and Deprotection:

The synthesized sequences are cleaved and deprotected in 96 well plates,using a mixture of aqueous and ethanolic methylamine (3:1 ratio) in thefirst step and triethylamine ³HF in the second step. The crude sequencesthus obtained are precipitated using acetone: ethanol mix and the pelletare re-suspended in 0.02M sodium acetate buffer. Samples from eachsequence are analyzed by LC-MS and the resulting mass data confirmed theidentity of the sequences. A selected set of samples are also analyzedby IEX chromatography.

Purification and Desalting:

All single strands are isolated as desalted solutions in water prior toannealing step. Sequences are purified on AKTA explorer purificationsystem using Source 15Q column. Purification is performed using a columnand in-line buffer heater set at 60° C. A single peak corresponding tothe full length sequence is collected in the eluant and is subsequentlyanalyzed for purity by ion exchange chromatography.

The purified sequences are desalted on a Sephadex G25 column using AKTApurifier. The desalted KRAS sequences are analyzed for concentration andpurity. The single strands are annealed on an automated platform to formsiRNA duplexes. Each duplex is made at a concentration of 10 μM in 1×PBSand are analyzed for purity by capillary gel electrophoresis. Details onindividual duplexes are provided in Tables 1 to 3. Some sequences inTable 2, and other tables herein, represent the DNA target of therecited RNAi agent (these DNA targets comprise DNA sequences, comprisingT, rather than RNA sequences, which comprise U).

TABLE 2 KRAS duplexes with unmodified sequences SEQ ID SEQ ID DuplexSense Seq NO: Antisense Seq NO: AD-35523.3 GGACGAAUAUGAUCCAACA 1UGUUGGAUCAUAUUCGUCC 428 AD-35529.1 GACGAAUAUGAUCCAACAA 2UUGUUGGAUCAUAUUCGUC 429 AD-35535.4 ACGAAUAUGAUCCAACAAU 3AUUGUUGGAUCAUAUUCGU 430 AD-35541.4 CGAAUAUGAUCCAACAAUA 4UAUUGUUGGAUCAUAUUCG 431 AD-35547.4 GAAUAUGAUCCAACAAUAG 5CUAUUGUUGGAUCAUAUUC 432 AD-35553.4 AAUAUGAUCCAACAAUAGA 6UCUAUUGUUGGAUCAUAUU 433 AD-35559.4 AUAUGAUCCAACAAUAGAG 7CUCUAUUGUUGGAUCAUAU 434 AD-35565.4 UAUGAUCCAACAAUAGAGG 8CCUCUAUUGUUGGAUCAUA 435 AD-35524.4 AUGAUCCAACAAUAGAGGA 9UCCUCUAUUGUUGGAUCAU 436 AD-35530.4 UGAUCCAACAAUAGAGGAU 10AUCCUCUAUUGUUGGAUCA 437 AD-35536.4 GAUCCAACAAUAGAGGAUU 11AAUCCUCUAUUGUUGGAUC 438 AD-35542.4 AUCCAACAAUAGAGGAUUC 12GAAUCCUCUAUUGUUGGAU 439 AD-35548.4 UCCAACAAUAGAGGAUUCC 13GGAAUCCUCUAUUGUUGGA 440 AD-35554.4 CCAACAAUAGAGGAUUCCU 14AGGAAUCCUCUAUUGUUGG 441 AD-35560.2 CAACAAUAGAGGAUUCCUA 15UAGGAAUCCUCUAUUGUUG 442 AD-35566.4 AACAAUAGAGGAUUCCUAC 16GUAGGAAUCCUCUAUUGUU 443 AD-35525.2 ACAAUAGAGGAUUCCUACA 17UGUAGGAAUCCUCUAUUGU 444 AD-35531.4 CAAUAGAGGAUUCCUACAG 18CUGUAGGAAUCCUCUAUUG 445 AD-35537.4 AAUAGAGGAUUCCUACAGG 19CCUGUAGGAAUCCUCUAUU 446 AD-35543.2 AUAGAGGAUUCCUACAGGA 20UCCUGUAGGAAUCCUCUAU 447 AD-35549.4 UAGAGGAUUCCUACAGGAA 21UUCCUGUAGGAAUCCUCUA 448 AD-35555.4 AGAGGAUUCCUACAGGAAG 22CUUCCUGUAGGAAUCCUCU 449 AD-35561.4 GAGGAUUCCUACAGGAAGC 23GCUUCCUGUAGGAAUCCUC 450 AD-35567.4 AGGAUUCCUACAGGAAGCA 24UGCUUCCUGUAGGAAUCCU 451 AD-35526.4 GGAUUCCUACAGGAAGCAA 25UUGCUUCCUGUAGGAAUCC 452 AD-35532.4 GAUUCCUACAGGAAGCAAG 26CUUGCUUCCUGUAGGAAUC 453 AD-35538.4 AUUCCUACAGGAAGCAAGU 27ACUUGCUUCCUGUAGGAAU 454 AD-35544.4 UUCCUACAGGAAGCAAGUA 28UACUUGCUUCCUGUAGGAA 455 AD-35550.4 UCCUACAGGAAGCAAGUAG 29CUACUUGCUUCCUGUAGGA 456 AD-35556.4 CCUACAGGAAGCAAGUAGU 30ACUACUUGCUUCCUGUAGG 457 AD-35562.4 CUACAGGAAGCAAGUAGUA 31UACUACUUGCUUCCUGUAG 458 AD-35568.4 UACAGGAAGCAAGUAGUAA 32UUACUACUUGCUUCCUGUA 459 AD-35527.4 ACAGGAAGCAAGUAGUAAU 33AUUACUACUUGCUUCCUGU 460 AD-35533.4 CAGGAAGCAAGUAGUAAUU 34AAUUACUACUUGCUUCCUG 461 AD-35539.4 UUGGAUAUUCUCGACACAG 35CUGUGUCGAGAAUAUCCAA 462 AD-35545.4 UGGAUAUUCUCGACACAGC 36GCUGUGUCGAGAAUAUCCA 463 AD-35551.4 GGAUAUUCUCGACACAGCA 37UGCUGUGUCGAGAAUAUCC 464 AD-35563.4 AUAUUCUCGACACAGCAGG 38CCUGCUGUGUCGAGAAUAU 465 AD-35528.4 AUUCUCGACACAGCAGGUC 39GACCUGCUGUGUCGAGAAU 466 AD-35540.4 UCUCGACACAGCAGGUCAA 40UUGACCUGCUGUGUCGAGA 467 AD-35546.4 CUCGACACAGCAGGUCAAG 41CUUGACCUGCUGUGUCGAG 468 AD-35552.4 UCGACACAGCAGGUCAAGA 42UCUUGACCUGCUGUGUCGA 469 AD-35558.4 CGACACAGCAGGUCAAGAG 43CUCUUGACCUGCUGUGUCG 470 AD-35564.4 GACACAGCAGGUCAAGAGG 44CCUCUUGACCUGCUGUGUC 471 AD-35570.4 ACACAGCAGGUCAAGAGGA 45UCCUCUUGACCUGCUGUGU 472 AD-35571.4 CACAGCAGGUCAAGAGGAG 46CUCCUCUUGACCUGCUGUG 473 AD-35577.4 ACAGCAGGUCAAGAGGAGU 47ACUCCUCUUGACCUGCUGU 474 AD-35583.4 CAGCAGGUCAAGAGGAGUA 48UACUCCUCUUGACCUGCUG 475 AD-35589.4 AGCAGGUCAAGAGGAGUAC 49GUACUCCUCUUGACCUGCU 476 AD-35595.4 GCAGGUCAAGAGGAGUACA 50UGUACUCCUCUUGACCUGC 477 AD-35601.4 CAGGUCAAGAGGAGUACAG 51CUGUACUCCUCUUGACCUG 478 AD-35607.4 AGGUCAAGAGGAGUACAGU 52ACUGUACUCCUCUUGACCU 479 AD-35613.4 GGUCAAGAGGAGUACAGUG 53CACUGUACUCCUCUUGACC 480 AD-35572.4 GUCAAGAGGAGUACAGUGC 54GCACUGUACUCCUCUUGAC 481 AD-35578.4 UCAAGAGGAGUACAGUGCA 55UGCACUGUACUCCUCUUGA 482 AD-35584.4 CAAGAGGAGUACAGUGCAA 56UUGCACUGUACUCCUCUUG 483 AD-35590.4 AAGAGGAGUACAGUGCAAU 57AUUGCACUGUACUCCUCUU 484 AD-35596.4 AGAGGAGUACAGUGCAAUG 58CAUUGCACUGUACUCCUCU 485 AD-35602.4 GAGGAGUACAGUGCAAUGA 59UCAUUGCACUGUACUCCUC 486 AD-35608.4 AGGAGUACAGUGCAAUGAG 60CUCAUUGCACUGUACUCCU 487 AD-35614.4 GGAGUACAGUGCAAUGAGG 61CCUCAUUGCACUGUACUCC 488 AD-35573.4 GAGUACAGUGCAAUGAGGG 62CCCUCAUUGCACUGUACUC 489 AD-35579.4 GGGGAGGGCUUUCUUUGUG 63CACAAAGAAAGCCCUCCCC 490 AD-35585.4 GGGAGGGCUUUCUUUGUGU 64ACACAAAGAAAGCCCUCCC 491 AD-35591.4 GGAGGGCUUUCUUUGUGUA 65UACACAAAGAAAGCCCUCC 492 AD-35597.4 GAGGGCUUUCUUUGUGUAU 66AUACACAAAGAAAGCCCUC 493 AD-35603.4 AGGGCUUUCUUUGUGUAUU 67AAUACACAAAGAAAGCCCU 494 AD-35609.4 GGGCUUUCUUUGUGUAUUU 68AAAUACACAAAGAAAGCCC 495 AD-35615.4 GGCUUUCUUUGUGUAUUUG 69CAAAUACACAAAGAAAGCC 496 AD-35574.4 GCUUUCUUUGUGUAUUUGC 70GCAAAUACACAAAGAAAGC 497 AD-35580.1 CUUUCUUUGUGUAUUUGCC 71GGCAAAUACACAAAGAAAG 498 AD-35586.4 UUUCUUUGUGUAUUUGCCA 72UGGCAAAUACACAAAGAAA 499 AD-35592.4 UUCUUUGUGUAUUUGCCAU 73AUGGCAAAUACACAAAGAA 500 AD-35598.4 UCUUUGUGUAUUUGCCAUA 74UAUGGCAAAUACACAAAGA 501 AD-35604.4 CUUUGUGUAUUUGCCAUAA 75UUAUGGCAAAUACACAAAG 502 AD-35610.4 UUUGUGUAUUUGCCAUAAA 76UUUAUGGCAAAUACACAAA 503 AD-35616.4 UUGUGUAUUUGCCAUAAAU 77AUUUAUGGCAAAUACACAA 504 AD-35575.4 UGUGUAUUUGCCAUAAAUA 78UAUUUAUGGCAAAUACACA 505 AD-35581.4 GUGUAUUUGCCAUAAAUAA 79UUAUUUAUGGCAAAUACAC 506 AD-35587.4 UGUAUUUGCCAUAAAUAAU 80AUUAUUUAUGGCAAAUACA 507 AD-35593.4 GUAUUUGCCAUAAAUAAUA 81UAUUAUUUAUGGCAAAUAC 508 AD-35599.4 UAUUUGCCAUAAAUAAUAC 82GUAUUAUUUAUGGCAAAUA 509 AD-35605.4 AUUUGCCAUAAAUAAUACU 83AGUAUUAUUUAUGGCAAAU 510 AD-35611.4 UUUGCCAUAAAUAAUACUA 84UAGUAUUAUUUAUGGCAAA 511 AD-35617.4 UGAAGAUAUUCACCAUUAU 85AUAAUGGUGAAUAUCUUCA 512 AD-35576.4 GAAGAUAUUCACCAUUAUA 86UAUAAUGGUGAAUAUCUUC 513 AD-35588.4 AGAUAUUCACCAUUAUAGA 87UCUAUAAUGGUGAAUAUCU 514 AD-35667.1 AAACAUCAGCAAAGACAAG 88CUUGUCUUUGCUGAUGUUU 515 AD-35673.1 AACAUCAGCAAAGACAAGA 89UCUUGUCUUUGCUGAUGUU 516 AD-35679.1 ACAUCAGCAAAGACAAGAC 90GUCUUGUCUUUGCUGAUGU 517 AD-35685.1 CAUCAGCAAAGACAAGACA 91UGUCUUGUCUUUGCUGAUG 518 AD-35691.1 AUCAGCAAAGACAAGACAG 92CUGUCUUGUCUUUGCUGAU 519 AD-35557.1 GAUAUUCUCGACACAGCAG 93CUGCUGUGUCGAGAAUAUC 520 AD-35618.1 UUCACCAUUAUAGAGAACA 94UGUUCUCUAUAAUGGUGAA 521 AD-35569.1 UAUUCUCGACACAGCAGGU 95ACCUGCUGUGUCGAGAAUA 522 AD-35534.1 UUCUCGACACAGCAGGUCA 96UGACCUGCUGUGUCGAGAA 523 AD-35582.1 AAGAUAUUCACCAUUAUAG 97CUAUAAUGGUGAAUAUCUU 524 AD-35594.1 GAUAUUCACCAUUAUAGAG 98CUCUAUAAUGGUGAAUAUC 525 AD-35600.1 AUAUUCACCAUUAUAGAGA 99UCUCUAUAAUGGUGAAUAU 526 AD-35606.1 UAUUCACCAUUAUAGAGAA 100UUCUCUAUAAUGGUGAAUA 527 AD-35612.1 AUUCACCAUUAUAGAGAAC 101GUUCUCUAUAAUGGUGAAU 528 AD-38127.1 UCACCAUUAUAGAGAACAA 102UUGUUCUCUAUAAUGGUGA 529 AD-38133.1 CACCAUUAUAGAGAACAAA 103UUUGUUCUCUAUAAUGGUG 530 AD-38139.1 ACCAUUAUAGAGAACAAAU 104AUUUGUUCUCUAUAAUGGU 531 AD-38145.1 CCAUUAUAGAGAACAAAUU 105AAUUUGUUCUCUAUAAUGG 532 AD-38151.1 CAUUAUAGAGAACAAAUUA 106UAAUUUGUUCUCUAUAAUG 533 AD-38157.1 AUUAUAGAGAACAAAUUAA 107UUAAUUUGUUCUCUAUAAU 534 AD-38163.1 UUAUAGAGAACAAAUUAAA 108UUUAAUUUGUUCUCUAUAA 535 AD-38169.1 UAUAGAGAACAAAUUAAAA 109UUUUAAUUUGUUCUCUAUA 536 AD-38128.1 AUAGAGAACAAAUUAAAAG 110CUUUUAAUUUGUUCUCUAU 537 AD-38134.1 UAGAGAACAAAUUAAAAGA 111UCUUUUAAUUUGUUCUCUA 538 AD-38140.1 AGAGAACAAAUUAAAAGAG 112CUCUUUUAAUUUGUUCUCU 539 AD-38146.1 GAAGAUGUACCUAUGGUCC 113GGACCAUAGGUACAUCUUC 540 AD-38152.1 AAGAUGUACCUAUGGUCCU 114AGGACCAUAGGUACAUCUU 541 AD-38158.1 AGAUGUACCUAUGGUCCUA 115UAGGACCAUAGGUACAUCU 542 AD-38164.1 GAUGUACCUAUGGUCCUAG 116CUAGGACCAUAGGUACAUC 543 AD-38170.1 AUGUACCUAUGGUCCUAGU 117ACUAGGACCAUAGGUACAU 544 AD-38129.1 UGUACCUAUGGUCCUAGUA 118UACUAGGACCAUAGGUACA 545 AD-38135.1 GUACCUAUGGUCCUAGUAG 119CUACUAGGACCAUAGGUAC 546 AD-38141.1 UACCUAUGGUCCUAGUAGG 120CCUACUAGGACCAUAGGUA 547 AD-38147.1 ACCUAUGGUCCUAGUAGGA 121UCCUACUAGGACCAUAGGU 548 AD-38153.1 CCUAUGGUCCUAGUAGGAA 122UUCCUACUAGGACCAUAGG 549 AD-38159.1 CUAUGGUCCUAGUAGGAAA 123UUUCCUACUAGGACCAUAG 550 AD-38165.1 UAUGGUCCUAGUAGGAAAU 124AUUUCCUACUAGGACCAUA 551 AD-38171.1 AUGGUCCUAGUAGGAAAUA 125UAUUUCCUACUAGGACCAU 552 AD-38130.1 UGGUCCUAGUAGGAAAUAA 126UUAUUUCCUACUAGGACCA 553 AD-38136.1 GGUCCUAGUAGGAAAUAAA 127UUUAUUUCCUACUAGGACC 554 AD-38142.1 GUCCUAGUAGGAAAUAAAU 128AUUUAUUUCCUACUAGGAC 555 AD-38148.1 UCCUAGUAGGAAAUAAAUG 129CAUUUAUUUCCUACUAGGA 556 AD-38154.1 CCUAGUAGGAAAUAAAUGU 130ACAUUUAUUUCCUACUAGG 557 AD-38160.1 CUAGUAGGAAAUAAAUGUG 131CACAUUUAUUUCCUACUAG 558 AD-38166.1 UAGUAGGAAAUAAAUGUGA 132UCACAUUUAUUUCCUACUA 559 AD-38172.1 AGUAGGAAAUAAAUGUGAU 133AUCACAUUUAUUUCCUACU 560 AD-38131.1 GGAAUUCCUUUUAUUGAAA 134UUUCAAUAAAAGGAAUUCC 561 AD-38137.1 GAAUUCCUUUUAUUGAAAC 135GUUUCAAUAAAAGGAAUUC 562 AD-38143.1 AAUUCCUUUUAUUGAAACA 136UGUUUCAAUAAAAGGAAUU 563 AD-38149.1 AUUCCUUUUAUUGAAACAU 137AUGUUUCAAUAAAAGGAAU 564 AD-38155.1 UUCCUUUUAUUGAAACAUC 138GAUGUUUCAAUAAAAGGAA 565 AD-38161.1 UCCUUUUAUUGAAACAUCA 139UGAUGUUUCAAUAAAAGGA 566 AD-38167.1 CCUUUUAUUGAAACAUCAG 140CUGAUGUUUCAAUAAAAGG 567 AD-38173.1 CUUUUAUUGAAACAUCAGC 141GCUGAUGUUUCAAUAAAAG 568 AD-38132.1 UUUUAUUGAAACAUCAGCA 142UGCUGAUGUUUCAAUAAAA 569 AD-38138.1 UUUAUUGAAACAUCAGCAA 143UUGCUGAUGUUUCAAUAAA 570 AD-38144.1 UUAUUGAAACAUCAGCAAA 144UUUGCUGAUGUUUCAAUAA 571 AD-38150.1 UAUUGAAACAUCAGCAAAG 145CUUUGCUGAUGUUUCAAUA 572 AD-38156.1 AUUGAAACAUCAGCAAAGA 146UCUUUGCUGAUGUUUCAAU 573 AD-38162.1 UUGAAACAUCAGCAAAGAC 147GUCUUUGCUGAUGUUUCAA 574 AD-38168.1 UGAAACAUCAGCAAAGACA 148UGUCUUUGCUGAUGUUUCA 575 AD-38174.1 GAAACAUCAGCAAAGACAA 149UUGUCUUUGCUGAUGUUUC 576 AD-39683.1 AUGACUGAAUAUAAACUUG 150CAAGUUUAUAUUCAGUCAU 577 AD-39689.1 UGACUGAAUAUAAACUUGU 151ACAAGUUUAUAUUCAGUCA 578 AD-39695.1 GACUGAAUAUAAACUUGUG 152CACAAGUUUAUAUUCAGUC 579 AD-39701.1 ACUGAAUAUAAACUUGUGG 153CCACAAGUUUAUAUUCAGU 580 AD-39707.1 CUGAAUAUAAACUUGUGGU 154ACCACAAGUUUAUAUUCAG 581 AD-39713.1 UGAAUAUAAACUUGUGGUA 155UACCACAAGUUUAUAUUCA 582 AD-39719.1 GAAUAUAAACUUGUGGUAG 156CUACCACAAGUUUAUAUUC 583 AD-39725.1 AAUAUAAACUUGUGGUAGU 157ACUACCACAAGUUUAUAUU 584 AD-39684.1 AUAUAAACUUGUGGUAGUU 158AACUACCACAAGUUUAUAU 585 AD-39690.1 UAUAAACUUGUGGUAGUUG 159CAACUACCACAAGUUUAUA 586 AD-39696.1 AUAAACUUGUGGUAGUUGG 160CCAACUACCACAAGUUUAU 587 AD-39702.1 UAAACUUGUGGUAGUUGGA 161UCCAACUACCACAAGUUUA 588 AD-39708.1 AAACUUGUGGUAGUUGGAG 162CUCCAACUACCACAAGUUU 589 AD-39714.1 AACUUGUGGUAGUUGGAGC 163GCUCCAACUACCACAAGUU 590 AD-39720.1 ACUUGUGGUAGUUGGAGCU 164AGCUCCAACUACCACAAGU 591 AD-39726.1 CUUGUGGUAGUUGGAGCUG 165CAGCUCCAACUACCACAAG 592 AD-39685.1 UUGUGGUAGUUGGAGCUGG 166CCAGCUCCAACUACCACAA 593 AD-39691.1 UGUGGUAGUUGGAGCUGGU 167ACCAGCUCCAACUACCACA 594 AD-39697.1 GUGGUAGUUGGAGCUGGUG 168CACCAGCUCCAACUACCAC 595 AD-39703.1 UGGUAGUUGGAGCUGGUGG 169CCACCAGCUCCAACUACCA 596 AD-39709.1 GGUAGUUGGAGCUGGUGGC 170GCCACCAGCUCCAACUACC 597 AD-39715.1 GUAGUUGGAGCUGGUGGCG 171CGCCACCAGCUCCAACUAC 598 AD-39721.1 UAGUUGGAGCUGGUGGCGU 172ACGCCACCAGCUCCAACUA 599 AD-39727.1 AGUUGGAGCUGGUGGCGUA 173UACGCCACCAGCUCCAACU 600 AD-39686.1 GUUGGAGCUGGUGGCGUAG 174CUACGCCACCAGCUCCAAC 601 AD-39692.1 UUGGAGCUGGUGGCGUAGG 175CCUACGCCACCAGCUCCAA 602 AD-39698.1 UGGAGCUGGUGGCGUAGGC 176GCCUACGCCACCAGCUCCA 603 AD-39704.1 GGAGCUGGUGGCGUAGGCA 177UGCCUACGCCACCAGCUCC 604 AD-39710.1 GAGCUGGUGGCGUAGGCAA 178UUGCCUACGCCACCAGCUC 605 AD-39716.1 AGCUGGUGGCGUAGGCAAG 179CUUGCCUACGCCACCAGCU 606 AD-39722.1 GCUGGUGGCGUAGGCAAGA 180UCUUGCCUACGCCACCAGC 607 AD-39728.1 CUGGUGGCGUAGGCAAGAG 181CUCUUGCCUACGCCACCAG 608 AD-39687.1 UGGUGGCGUAGGCAAGAGU 182ACUCUUGCCUACGCCACCA 609 AD-39693.1 GGUGGCGUAGGCAAGAGUG 183CACUCUUGCCUACGCCACC 610 AD-39699.1 GUGGCGUAGGCAAGAGUGC 184GCACUCUUGCCUACGCCAC 611 AD-39705.1 UGGCGUAGGCAAGAGUGCC 185GGCACUCUUGCCUACGCCA 612 AD-39711.1 GGCGUAGGCAAGAGUGCCU 186AGGCACUCUUGCCUACGCC 613 AD-39717.1 GCGUAGGCAAGAGUGCCUU 187AAGGCACUCUUGCCUACGC 614 AD-39723.1 CGUAGGCAAGAGUGCCUUG 188CAAGGCACUCUUGCCUACG 615 AD-39729.1 GUAGGCAAGAGUGCCUUGA 189UCAAGGCACUCUUGCCUAC 616 AD-39688.1 UAGGCAAGAGUGCCUUGAC 190GUCAAGGCACUCUUGCCUA 617 AD-39694.1 AGGCAAGAGUGCCUUGACG 191CGUCAAGGCACUCUUGCCU 618 AD-39700.1 GGCAAGAGUGCCUUGACGA 192UCGUCAAGGCACUCUUGCC 619 AD-39706.1 GCAAGAGUGCCUUGACGAU 193AUCGUCAAGGCACUCUUGC 620 AD-39712.1 CAAGAGUGCCUUGACGAUA 194UAUCGUCAAGGCACUCUUG 621 AD-39718.1 AAGAGUGCCUUGACGAUAC 195GUAUCGUCAAGGCACUCUU 622 AD-39724.1 AGAGUGCCUUGACGAUACA 196UGUAUCGUCAAGGCACUCU 623 AD-39730.1 GAGUGCCUUGACGAUACAG 197CUGUAUCGUCAAGGCACUC 624 AD-39736.1 AGUGCCUUGACGAUACAGC 198GCUGUAUCGUCAAGGCACU 625 AD-39742.1 GUGCCUUGACGAUACAGCU 199AGCUGUAUCGUCAAGGCAC 626 AD-39748.1 UGCCUUGACGAUACAGCUA 200UAGCUGUAUCGUCAAGGCA 627 AD-39754.1 GCCUUGACGAUACAGCUAA 201UUAGCUGUAUCGUCAAGGC 628 AD-39760.1 CCUUGACGAUACAGCUAAU 202AUUAGCUGUAUCGUCAAGG 629 AD-39766.1 CUUGACGAUACAGCUAAUU 203AAUUAGCUGUAUCGUCAAG 630 AD-39772.1 UUGACGAUACAGCUAAUUC 204GAAUUAGCUGUAUCGUCAA 631 AD-39731.1 UGACGAUACAGCUAAUUCA 205UGAAUUAGCUGUAUCGUCA 632 AD-39737.1 GACGAUACAGCUAAUUCAG 206CUGAAUUAGCUGUAUCGUC 633 AD-39743.1 ACGAUACAGCUAAUUCAGA 207UCUGAAUUAGCUGUAUCGU 634 AD-39749.1 CGAUACAGCUAAUUCAGAA 208UUCUGAAUUAGCUGUAUCG 635 AD-39755.1 GAUACAGCUAAUUCAGAAU 209AUUCUGAAUUAGCUGUAUC 636 AD-39761.1 AUACAGCUAAUUCAGAAUC 210GAUUCUGAAUUAGCUGUAU 637 AD-39767.1 UACAGCUAAUUCAGAAUCA 211UGAUUCUGAAUUAGCUGUA 638 AD-39773.1 ACAGCUAAUUCAGAAUCAU 212AUGAUUCUGAAUUAGCUGU 639 AD-39732.1 CAGCUAAUUCAGAAUCAUU 213AAUGAUUCUGAAUUAGCUG 640 AD-39738.1 AGCUAAUUCAGAAUCAUUU 214AAAUGAUUCUGAAUUAGCU 641 AD-39744.1 GCUAAUUCAGAAUCAUUUU 215AAAAUGAUUCUGAAUUAGC 642 AD-39750.1 CUAAUUCAGAAUCAUUUUG 216CAAAAUGAUUCUGAAUUAG 643 AD-39756.1 UAAUUCAGAAUCAUUUUGU 217ACAAAAUGAUUCUGAAUUA 644 AD-39762.1 AAUUCAGAAUCAUUUUGUG 218CACAAAAUGAUUCUGAAUU 645 AD-39768.1 AUUCAGAAUCAUUUUGUGG 219CCACAAAAUGAUUCUGAAU 646 AD-39774.1 UUCAGAAUCAUUUUGUGGA 220UCCACAAAAUGAUUCUGAA 647 AD-39733.1 UCAGAAUCAUUUUGUGGAC 221GUCCACAAAAUGAUUCUGA 648 AD-39739.1 CAGAAUCAUUUUGUGGACG 222CGUCCACAAAAUGAUUCUG 649 AD-39745.1 AGAAUCAUUUUGUGGACGA 223UCGUCCACAAAAUGAUUCU 650 AD-39751.1 GAAUCAUUUUGUGGACGAA 224UUCGUCCACAAAAUGAUUC 651 AD-39757.1 AAUCAUUUUGUGGACGAAU 225AUUCGUCCACAAAAUGAUU 652 AD-39763.1 AUCAUUUUGUGGACGAAUA 226UAUUCGUCCACAAAAUGAU 653 AD-39769.1 UCAUUUUGUGGACGAAUAU 227AUAUUCGUCCACAAAAUGA 654 AD-39775.1 CAUUUUGUGGACGAAUAUG 228CAUAUUCGUCCACAAAAUG 655 AD-39734.1 AUUUUGUGGACGAAUAUGA 229UCAUAUUCGUCCACAAAAU 656 AD-39740.1 UUUUGUGGACGAAUAUGAU 230AUCAUAUUCGUCCACAAAA 657 AD-39746.1 UUUGUGGACGAAUAUGAUC 231GAUCAUAUUCGUCCACAAA 658 AD-39752.1 UUGUGGACGAAUAUGAUCC 232GGAUCAUAUUCGUCCACAA 659 AD-39758.1 UGUGGACGAAUAUGAUCCA 233UGGAUCAUAUUCGUCCACA 660 AD-39764.1 GUGGACGAAUAUGAUCCAA 234UUGGAUCAUAUUCGUCCAC 661 AD-39770.1 UGGACGAAUAUGAUCCAAC 235GUUGGAUCAUAUUCGUCCA 662 AD-39776.1 AGGAAGCAAGUAGUAAUUG 236CAAUUACUACUUGCUUCCU 663 AD-39735.1 GGAAGCAAGUAGUAAUUGA 237UCAAUUACUACUUGCUUCC 664 AD-39741.1 GAAGCAAGUAGUAAUUGAU 238AUCAAUUACUACUUGCUUC 665 AD-39747.1 AAGCAAGUAGUAAUUGAUG 239CAUCAAUUACUACUUGCUU 666 AD-39753.1 AGCAAGUAGUAAUUGAUGG 240CCAUCAAUUACUACUUGCU 667 AD-39759.1 GCAAGUAGUAAUUGAUGGA 241UCCAUCAAUUACUACUUGC 668 AD-39765.1 CAAGUAGUAAUUGAUGGAG 242CUCCAUCAAUUACUACUUG 669 AD-39771.1 AAGUAGUAAUUGAUGGAGA 243UCUCCAUCAAUUACUACUU 670 AD-39778.1 AGUAGUAAUUGAUGGAGAA 244UUCUCCAUCAAUUACUACU 671 AD-39784.1 GUAGUAAUUGAUGGAGAAA 245UUUCUCCAUCAAUUACUAC 672 AD-39790.1 UAGUAAUUGAUGGAGAAAC 246GUUUCUCCAUCAAUUACUA 673 AD-39796.1 AGUAAUUGAUGGAGAAACC 247GGUUUCUCCAUCAAUUACU 674 AD-39802.1 GUAAUUGAUGGAGAAACCU 248AGGUUUCUCCAUCAAUUAC 675 AD-39808.1 UAAUUGAUGGAGAAACCUG 249CAGGUUUCUCCAUCAAUUA 676 AD-39814.1 AAUUGAUGGAGAAACCUGU 250ACAGGUUUCUCCAUCAAUU 677 AD-39820.1 AUUGAUGGAGAAACCUGUC 251GACAGGUUUCUCCAUCAAU 678 AD-39779.1 UUGAUGGAGAAACCUGUCU 252AGACAGGUUUCUCCAUCAA 679 AD-39785.1 UGAUGGAGAAACCUGUCUC 253GAGACAGGUUUCUCCAUCA 680 AD-39791.1 GAUGGAGAAACCUGUCUCU 254AGAGACAGGUUUCUCCAUC 681 AD-39797.1 AUGGAGAAACCUGUCUCUU 255AAGAGACAGGUUUCUCCAU 682 AD-39803.1 UGGAGAAACCUGUCUCUUG 256CAAGAGACAGGUUUCUCCA 683 AD-39809.1 GGAGAAACCUGUCUCUUGG 257CCAAGAGACAGGUUUCUCC 684 AD-39815.1 GAGAAACCUGUCUCUUGGA 258UCCAAGAGACAGGUUUCUC 685 AD-39821.1 AGAAACCUGUCUCUUGGAU 259AUCCAAGAGACAGGUUUCU 686 AD-39780.1 GAAACCUGUCUCUUGGAUA 260UAUCCAAGAGACAGGUUUC 687 AD-39786.1 AAACCUGUCUCUUGGAUAU 261AUAUCCAAGAGACAGGUUU 688 AD-39792.1 AACCUGUCUCUUGGAUAUU 262AAUAUCCAAGAGACAGGUU 689 AD-39798.1 ACCUGUCUCUUGGAUAUUC 263GAAUAUCCAAGAGACAGGU 690 AD-39804.1 CCUGUCUCUUGGAUAUUCU 264AGAAUAUCCAAGAGACAGG 691 AD-39810.1 CUGUCUCUUGGAUAUUCUC 265GAGAAUAUCCAAGAGACAG 692 AD-39816.1 UGUCUCUUGGAUAUUCUCG 266CGAGAAUAUCCAAGAGACA 693 AD-39822.1 GUCUCUUGGAUAUUCUCGA 267UCGAGAAUAUCCAAGAGAC 694 AD-39781.1 UCUCUUGGAUAUUCUCGAC 268GUCGAGAAUAUCCAAGAGA 695 AD-39787.1 CUCUUGGAUAUUCUCGACA 269UGUCGAGAAUAUCCAAGAG 696 AD-39793.1 UCUUGGAUAUUCUCGACAC 270GUGUCGAGAAUAUCCAAGA 697 AD-39799.1 CUUGGAUAUUCUCGACACA 271UGUGUCGAGAAUAUCCAAG 698 AD-39805.1 AGUACAGUGCAAUGAGGGA 272UCCCUCAUUGCACUGUACU 699 AD-39811.1 GUACAGUGCAAUGAGGGAC 273GUCCCUCAUUGCACUGUAC 700 AD-39817.1 UACAGUGCAAUGAGGGACC 274GGUCCCUCAUUGCACUGUA 701 AD-39823.1 ACAGUGCAAUGAGGGACCA 275UGGUCCCUCAUUGCACUGU 702 AD-39782.1 CAGUGCAAUGAGGGACCAG 276CUGGUCCCUCAUUGCACUG 703 AD-39788.1 AGUGCAAUGAGGGACCAGU 277ACUGGUCCCUCAUUGCACU 704 AD-39794.1 GUGCAAUGAGGGACCAGUA 278UACUGGUCCCUCAUUGCAC 705 AD-39800.1 UGCAAUGAGGGACCAGUAC 279GUACUGGUCCCUCAUUGCA 706 AD-39806.1 GCAAUGAGGGACCAGUACA 280UGUACUGGUCCCUCAUUGC 707 AD-39812.1 CAAUGAGGGACCAGUACAU 281AUGUACUGGUCCCUCAUUG 708 AD-39818.1 AAUGAGGGACCAGUACAUG 282CAUGUACUGGUCCCUCAUU 709 AD-39824.1 AUGAGGGACCAGUACAUGA 283UCAUGUACUGGUCCCUCAU 710 AD-39783.1 UGAGGGACCAGUACAUGAG 284CUCAUGUACUGGUCCCUCA 711 AD-39789.1 GAGGGACCAGUACAUGAGG 285CCUCAUGUACUGGUCCCUC 712 AD-39795.1 AGGGACCAGUACAUGAGGA 286UCCUCAUGUACUGGUCCCU 713 AD-39801.1 GGGACCAGUACAUGAGGAC 287GUCCUCAUGUACUGGUCCC 714 AD-39807.1 GGACCAGUACAUGAGGACU 288AGUCCUCAUGUACUGGUCC 715 AD-39813.1 GACCAGUACAUGAGGACUG 289CAGUCCUCAUGUACUGGUC 716 AD-39819.1 ACCAGUACAUGAGGACUGG 290CCAGUCCUCAUGUACUGGU 717 AD-39825.1 CCAGUACAUGAGGACUGGG 291CCCAGUCCUCAUGUACUGG 718 AD-39831.1 CAGUACAUGAGGACUGGGG 292CCCCAGUCCUCAUGUACUG 719 AD-39837.1 AGUACAUGAGGACUGGGGA 293UCCCCAGUCCUCAUGUACU 720 AD-39843.1 GUACAUGAGGACUGGGGAG 294CUCCCCAGUCCUCAUGUAC 721 AD-39849.1 UACAUGAGGACUGGGGAGG 295CCUCCCCAGUCCUCAUGUA 722 AD-39855.1 ACAUGAGGACUGGGGAGGG 296CCCUCCCCAGUCCUCAUGU 723 AD-39861.1 CAUGAGGACUGGGGAGGGC 297GCCCUCCCCAGUCCUCAUG 724 AD-39867.1 AUGAGGACUGGGGAGGGCU 298AGCCCUCCCCAGUCCUCAU 725 AD-39826.1 UGAGGACUGGGGAGGGCUU 299AAGCCCUCCCCAGUCCUCA 726 AD-39832.1 GAGGACUGGGGAGGGCUUU 300AAAGCCCUCCCCAGUCCUC 727 AD-39838.1 AGGACUGGGGAGGGCUUUC 301GAAAGCCCUCCCCAGUCCU 728 AD-39844.1 GGACUGGGGAGGGCUUUCU 302AGAAAGCCCUCCCCAGUCC 729 AD-39850.1 GACUGGGGAGGGCUUUCUU 303AAGAAAGCCCUCCCCAGUC 730 AD-39856.1 ACUGGGGAGGGCUUUCUUU 304AAAGAAAGCCCUCCCCAGU 731 AD-39862.1 CUGGGGAGGGCUUUCUUUG 305CAAAGAAAGCCCUCCCCAG 732 AD-39868.1 UGGGGAGGGCUUUCUUUGU 306ACAAAGAAAGCCCUCCCCA 733 AD-39827.1 UUGCCAUAAAUAAUACUAA 307UUAGUAUUAUUUAUGGCAA 734 AD-39833.1 UGCCAUAAAUAAUACUAAA 308UUUAGUAUUAUUUAUGGCA 735 AD-39839.1 GCCAUAAAUAAUACUAAAU 309AUUUAGUAUUAUUUAUGGC 736 AD-39845.1 CCAUAAAUAAUACUAAAUC 310GAUUUAGUAUUAUUUAUGG 737 AD-39851.1 CAUAAAUAAUACUAAAUCA 311UGAUUUAGUAUUAUUUAUG 738 AD-39857.1 AUAAAUAAUACUAAAUCAU 312AUGAUUUAGUAUUAUUUAU 739 AD-39863.1 UAAAUAAUACUAAAUCAUU 313AAUGAUUUAGUAUUAUUUA 740 AD-39869.1 AAAUAAUACUAAAUCAUUU 314AAAUGAUUUAGUAUUAUUU 741 AD-39828.1 AAUAAUACUAAAUCAUUUG 315CAAAUGAUUUAGUAUUAUU 742 AD-39834.1 AUAAUACUAAAUCAUUUGA 316UCAAAUGAUUUAGUAUUAU 743 AD-39840.1 UAAUACUAAAUCAUUUGAA 317UUCAAAUGAUUUAGUAUUA 744 AD-39846.1 AAUACUAAAUCAUUUGAAG 318CUUCAAAUGAUUUAGUAUU 745 AD-39852.1 AUACUAAAUCAUUUGAAGA 319UCUUCAAAUGAUUUAGUAU 746 AD-39858.1 UACUAAAUCAUUUGAAGAU 320AUCUUCAAAUGAUUUAGUA 747 AD-39864.1 ACUAAAUCAUUUGAAGAUA 321UAUCUUCAAAUGAUUUAGU 748 AD-39870.1 CUAAAUCAUUUGAAGAUAU 322AUAUCUUCAAAUGAUUUAG 749 AD-39829.1 UAAAUCAUUUGAAGAUAUU 323AAUAUCUUCAAAUGAUUUA 750 AD-39835.1 AAAUCAUUUGAAGAUAUUC 324GAAUAUCUUCAAAUGAUUU 751 AD-39841.1 AAUCAUUUGAAGAUAUUCA 325UGAAUAUCUUCAAAUGAUU 752 AD-39853.1 UCAUUUGAAGAUAUUCACC 326GGUGAAUAUCUUCAAAUGA 753 AD-39859.1 CAUUUGAAGAUAUUCACCA 327UGGUGAAUAUCUUCAAAUG 754 AD-39865.1 AUUUGAAGAUAUUCACCAU 328AUGGUGAAUAUCUUCAAAU 755 AD-39871.1 UUUGAAGAUAUUCACCAUU 329AAUGGUGAAUAUCUUCAAA 756 AD-39830.1 UUGAAGAUAUUCACCAUUA 330UAAUGGUGAAUAUCUUCAA 757 AD-39836.1 GAGAACAAAUUAAAAGAGU 331ACUCUUUUAAUUUGUUCUC 758 AD-39842.1 AGAACAAAUUAAAAGAGUU 332AACUCUUUUAAUUUGUUCU 759 AD-39848.1 GAACAAAUUAAAAGAGUUA 333UAACUCUUUUAAUUUGUUC 760 AD-39854.1 AACAAAUUAAAAGAGUUAA 334UUAACUCUUUUAAUUUGUU 761 AD-39860.1 ACAAAUUAAAAGAGUUAAG 335CUUAACUCUUUUAAUUUGU 762 AD-39866.1 CAAAUUAAAAGAGUUAAGG 336CCUUAACUCUUUUAAUUUG 763 AD-39992.1 AAAUUAAAAGAGUUAAGGA 337UCCUUAACUCUUUUAAUUU 764 AD-39998.1 AAUUAAAAGAGUUAAGGAC 338GUCCUUAACUCUUUUAAUU 765 AD-40004.1 AUUAAAAGAGUUAAGGACU 339AGUCCUUAACUCUUUUAAU 766 AD-40010.1 UUAAAAGAGUUAAGGACUC 340GAGUCCUUAACUCUUUUAA 767 AD-40016.1 UAAAAGAGUUAAGGACUCU 341AGAGUCCUUAACUCUUUUA 768 AD-40022.1 AAAAGAGUUAAGGACUCUG 342CAGAGUCCUUAACUCUUUU 769 AD-40028.1 AAAGAGUUAAGGACUCUGA 343UCAGAGUCCUUAACUCUUU 770 AD-40034.1 AAGAGUUAAGGACUCUGAA 344UUCAGAGUCCUUAACUCUU 771 AD-39999.1 GAGUUAAGGACUCUGAAGA 345UCUUCAGAGUCCUUAACUC 772 AD-40005.1 AGUUAAGGACUCUGAAGAU 346AUCUUCAGAGUCCUUAACU 773 AD-40011.1 GUUAAGGACUCUGAAGAUG 347CAUCUUCAGAGUCCUUAAC 774 AD-40017.1 UUAAGGACUCUGAAGAUGU 348ACAUCUUCAGAGUCCUUAA 775 AD-40029.1 AAGGACUCUGAAGAUGUAC 349GUACAUCUUCAGAGUCCUU 776 AD-40035.1 AGGACUCUGAAGAUGUACC 350GGUACAUCUUCAGAGUCCU 777 AD-39994.1 GGACUCUGAAGAUGUACCU 351AGGUACAUCUUCAGAGUCC 778 AD-40000.1 GACUCUGAAGAUGUACCUA 352UAGGUACAUCUUCAGAGUC 779 AD-40006.1 ACUCUGAAGAUGUACCUAU 353AUAGGUACAUCUUCAGAGU 780 AD-40012.1 CUCUGAAGAUGUACCUAUG 354CAUAGGUACAUCUUCAGAG 781 AD-40018.1 UCUGAAGAUGUACCUAUGG 355CCAUAGGUACAUCUUCAGA 782 AD-40024.1 CUGAAGAUGUACCUAUGGU 356ACCAUAGGUACAUCUUCAG 783 AD-40030.1 UGAAGAUGUACCUAUGGUC 357GACCAUAGGUACAUCUUCA 784 AD-40036.1 GUAGGAAAUAAAUGUGAUU 358AAUCACAUUUAUUUCCUAC 785 AD-39995.1 UAGGAAAUAAAUGUGAUUU 359AAAUCACAUUUAUUUCCUA 786 AD-40001.1 AGGAAAUAAAUGUGAUUUG 360CAAAUCACAUUUAUUUCCU 787 AD-40007.1 GGAAAUAAAUGUGAUUUGC 361GCAAAUCACAUUUAUUUCC 788 AD-40013.1 GAAAUAAAUGUGAUUUGCC 362GGCAAAUCACAUUUAUUUC 789 AD-40019.1 AAAUAAAUGUGAUUUGCCU 363AGGCAAAUCACAUUUAUUU 790 AD-40025.1 AAUAAAUGUGAUUUGCCUU 364AAGGCAAAUCACAUUUAUU 791 AD-40031.1 AUAAAUGUGAUUUGCCUUC 365GAAGGCAAAUCACAUUUAU 792 AD-40037.1 UAAAUGUGAUUUGCCUUCU 366AGAAGGCAAAUCACAUUUA 793 AD-39996.1 AAAUGUGAUUUGCCUUCUA 367UAGAAGGCAAAUCACAUUU 794 AD-40002.1 AAUGUGAUUUGCCUUCUAG 368CUAGAAGGCAAAUCACAUU 795 AD-40008.1 AUGUGAUUUGCCUUCUAGA 369UCUAGAAGGCAAAUCACAU 796 AD-40014.1 UGUGAUUUGCCUUCUAGAA 370UUCUAGAAGGCAAAUCACA 797 AD-40020.1 GUGAUUUGCCUUCUAGAAC 371GUUCUAGAAGGCAAAUCAC 798 AD-40026.1 UGAUUUGCCUUCUAGAACA 372UGUUCUAGAAGGCAAAUCA 799 AD-40032.1 GAUUUGCCUUCUAGAACAG 373CUGUUCUAGAAGGCAAAUC 800 AD-40038.1 AUUUGCCUUCUAGAACAGU 374ACUGUUCUAGAAGGCAAAU 801 AD-39997.1 UUUGCCUUCUAGAACAGUA 375UACUGUUCUAGAAGGCAAA 802 AD-40009.1 UGCCUUCUAGAACAGUAGA 376UCUACUGUUCUAGAAGGCA 803 AD-40015.1 GCCUUCUAGAACAGUAGAC 377GUCUACUGUUCUAGAAGGC 804 AD-40021.1 CCUUCUAGAACAGUAGACA 378UGUCUACUGUUCUAGAAGG 805 AD-40027.1 CUUCUAGAACAGUAGACAC 379GUGUCUACUGUUCUAGAAG 806 AD-40033.1 UUCUAGAACAGUAGACACA 380UGUGUCUACUGUUCUAGAA 807 AD-40039.1 UCUAGAACAGUAGACACAA 381UUGUGUCUACUGUUCUAGA 808 AD-40045.1 CUAGAACAGUAGACACAAA 382UUUGUGUCUACUGUUCUAG 809 AD-40051.1 UAGAACAGUAGACACAAAA 383UUUUGUGUCUACUGUUCUA 810 AD-40057.1 AGAACAGUAGACACAAAAC 384GUUUUGUGUCUACUGUUCU 811 AD-40063.1 GAACAGUAGACACAAAACA 385UGUUUUGUGUCUACUGUUC 812 AD-40069.1 AACAGUAGACACAAAACAG 386CUGUUUUGUGUCUACUGUU 813 AD-40075.1 ACAGUAGACACAAAACAGG 387CCUGUUUUGUGUCUACUGU 814 AD-40081.1 CAGUAGACACAAAACAGGC 388GCCUGUUUUGUGUCUACUG 815 AD-40040.1 AGUAGACACAAAACAGGCU 389AGCCUGUUUUGUGUCUACU 816 AD-40046.1 GUAGACACAAAACAGGCUC 390GAGCCUGUUUUGUGUCUAC 817 AD-40052.1 UAGACACAAAACAGGCUCA 391UGAGCCUGUUUUGUGUCUA 818 AD-40058.1 AGACACAAAACAGGCUCAG 392CUGAGCCUGUUUUGUGUCU 819 AD-40064.1 GACACAAAACAGGCUCAGG 393CCUGAGCCUGUUUUGUGUC 820 AD-40070.1 ACACAAAACAGGCUCAGGA 394UCCUGAGCCUGUUUUGUGU 821 AD-40076.1 CACAAAACAGGCUCAGGAC 395GUCCUGAGCCUGUUUUGUG 822 AD-40082.1 ACAAAACAGGCUCAGGACU 396AGUCCUGAGCCUGUUUUGU 823 AD-40041.1 CAAAACAGGCUCAGGACUU 397AAGUCCUGAGCCUGUUUUG 824 AD-40047.1 AAAACAGGCUCAGGACUUA 398UAAGUCCUGAGCCUGUUUU 825 AD-40053.1 AAACAGGCUCAGGACUUAG 399CUAAGUCCUGAGCCUGUUU 826 AD-40059.1 AACAGGCUCAGGACUUAGC 400GCUAAGUCCUGAGCCUGUU 827 AD-40065.1 ACAGGCUCAGGACUUAGCA 401UGCUAAGUCCUGAGCCUGU 828 AD-40071.1 CAGGCUCAGGACUUAGCAA 402UUGCUAAGUCCUGAGCCUG 829 AD-40077.1 AGGCUCAGGACUUAGCAAG 403CUUGCUAAGUCCUGAGCCU 830 AD-40083.1 GGCUCAGGACUUAGCAAGA 404UCUUGCUAAGUCCUGAGCC 831 AD-40042.1 GCUCAGGACUUAGCAAGAA 405UUCUUGCUAAGUCCUGAGC 832 AD-40048.1 CUCAGGACUUAGCAAGAAG 406CUUCUUGCUAAGUCCUGAG 833 AD-40054.1 UCAGGACUUAGCAAGAAGU 407ACUUCUUGCUAAGUCCUGA 834 AD-40060.1 CAGGACUUAGCAAGAAGUU 408AACUUCUUGCUAAGUCCUG 835 AD-40066.1 AGGACUUAGCAAGAAGUUA 409UAACUUCUUGCUAAGUCCU 836 AD-40072.1 GGACUUAGCAAGAAGUUAU 410AUAACUUCUUGCUAAGUCC 837 AD-40078.1 GACUUAGCAAGAAGUUAUG 411CAUAACUUCUUGCUAAGUC 838 AD-40084.1 ACUUAGCAAGAAGUUAUGG 412CCAUAACUUCUUGCUAAGU 839 AD-40043.1 CUUAGCAAGAAGUUAUGGA 413UCCAUAACUUCUUGCUAAG 840 AD-40049.1 UUAGCAAGAAGUUAUGGAA 414UUCCAUAACUUCUUGCUAA 841 AD-40055.1 UAGCAAGAAGUUAUGGAAU 415AUUCCAUAACUUCUUGCUA 842 AD-40061.1 AGCAAGAAGUUAUGGAAUU 416AAUUCCAUAACUUCUUGCU 843 AD-40067.1 GCAAGAAGUUAUGGAAUUC 417GAAUUCCAUAACUUCUUGC 844 AD-40073.1 CAAGAAGUUAUGGAAUUCC 418GGAAUUCCAUAACUUCUUG 845 AD-40079.1 AAGAAGUUAUGGAAUUCCU 419AGGAAUUCCAUAACUUCUU 846 AD-40085.1 AGAAGUUAUGGAAUUCCUU 420AAGGAAUUCCAUAACUUCU 847 AD-40044.1 GAAGUUAUGGAAUUCCUUU 421AAAGGAAUUCCAUAACUUC 848 AD-40050.1 AAGUUAUGGAAUUCCUUUU 422AAAAGGAAUUCCAUAACUU 849 AD-40056.1 AGUUAUGGAAUUCCUUUUA 423UAAAAGGAAUUCCAUAACU 850 AD-40062.1 GUUAUGGAAUUCCUUUUAU 424AUAAAAGGAAUUCCAUAAC 851 AD-40068.1 UUAUGGAAUUCCUUUUAUU 425AAUAAAAGGAAUUCCAUAA 852 AD-40074.1 UAUGGAAUUCCUUUUAUUG 426CAAUAAAAGGAAUUCCAUA 853 AD-40080.1 AUGGAAUUCCUUUUAUUGA 427UCAAUAAAAGGAAUUCCAU 854 AD-39720.1 ACTTGTGGTAGTTGGAGCT 1716AGCTCCAACTACCACAAGT 1754 AD-39706.1 GCAAGAGTGCCTTGACGAT 1717ATCGTCAAGGCACTCTTGC 1755 AD-39712.1 CAAGAGTGCCTTGACGATA 1718TATCGTCAAGGCACTCTTG 1756 AD-39760.1 CCTTGACGATACAGCTAAT 1719ATTAGCTGTATCGTCAAGG 1757 AD-39732.1 CAGCTAATTCAGAATCATT 1720AATGATTCTGAATTAGCTG 1758 AD-35541.4 CGAATATGATCCAACAATA 1721TATTGTTGGATCATATTCG 1759 AD-39735.1 GGAAGCAAGTAGTAATTGA 1722TCAATTACTACTTGCTTCC 1760 or hs_KRAS_321_A22S26 AD-39741.1GAAGCAAGTAGTAATTGAT 1723 ATCAATTACTACTTGCTTC 1761 or hs_KRAS_322_A22S26AD-39778.1 AGTAGTAATTGATGGAGAA 1724 TTCTCCATCAATTACTACT 1762 AD-39790.1TAGTAATTGATGGAGAAAC 1725 GTTTCTCCATCAATTACTA 1763 AD-39822.1GTCTCTTGGATATTCTCGA 1726 TCGAGAATATCCAAGAGAC 1764 AD-35609.4GGGCTTTCTTTGTGTATTT 1727 AAATACACAAAGAAAGCCC 1765 AD-35581.4GTGTATTTGCCATAAATAA 1728 TTATTTATGGCAAATACAC 1766 AD-39845.1CCATAAATAATACTAAATC 1729 GATTTAGTATTATTTATGG 1767 AD-39858.1TACTAAATCATTTGAAGAT 1730 ATCTTCAAATGATTTAGTA 1768 AD-39870.1CTAAATCATTTGAAGATAT 1731 ATATCTTCAAATGATTTAG 1769 AD-35576.4GAAGATATTCACCATTATA 1732 TATAATGGTGAATATCTTC 1770 AD-35588.4AGATATTCACCATTATAGA 1733 TCTATAATGGTGAATATCT 1771 AD-35600.1ATATTCACCATTATAGAGA 1734 TCTCTATAATGGTGAATAT 1772 AD-35606.1TATTCACCATTATAGAGAA 1735 TTCTCTATAATGGTGAATA 1773 AD-38151.1CATTATAGAGAACAAATTA 1736 TAATTTGTTCTCTATAATG 1774 AD-38163.1TTATAGAGAACAAATTAAA 1737 TTTAATTTGTTCTCTATAA 1775 AD-39999.1GAGTTAAGGACTCTGAAGA 1738 TCTTCAGAGTCCTTAACTC 1776 AD-38159.1CTATGGTCCTAGTAGGAAA 1739 TTTCCTACTAGGACCATAG 1777 or hs_KRAS_528_A22S26AD-38130.1 TGGTCCTAGTAGGAAATAA 1740 TTATTTCCTACTAGGACCA 1778 orhs_KRAS_531_A22S26 AD-38136.1 GGTCCTAGTAGGAAATAAA 1741TTTATTTCCTACTAGGACC 1779 AD-40036.1 GTAGGAAATAAATGTGATT 1742AATCACATTTATTTCCTAC 1780 AD-40008.1 ATGTGATTTGCCTTCTAGA 1743TCTAGAAGGCAAATCACAT 1781 AD-40021.1 CCTTCTAGAACAGTAGACA 1744TGTCTACTGTTCTAGAAGG 1782 AD-40077.1 AGGCTCAGGACTTAGCAAG 1745CTTGCTAAGTCCTGAGCCT 1783 AD-40072.1 GGACTTAGCAAGAAGTTAT 1746ATAACTTCTTGCTAAGTCC 1784 AD-40061.1 AGCAAGAAGTTATGGAATT 1747AATTCCATAACTTCTTGCT 1785 AD-40068.1 TTATGGAATTCCTTTTATT 1748AATAAAAGGAATTCCATAA 1786 AD-38131.1 GGAATTCCTTTTATTGAAA 1749TTTCAATAAAAGGAATTCC 1787 AD-38167.1 CCTTTTATTGAAACATCAG 1750CTGATGTTTCAATAAAAGG 1788 hs_KRAS CCTGATGAATGTAAAGTTA 1751TAACTTTACATTCATCAGG 1789 1273_A22S26 hs_KRAS GGAGAATTTAATAAAGATA 1752TATCTTTATTAAATTCTCC 1790 2892_A37S26 hs_KRAS GAATAGTCATAACTAGATT 1753AATCTAGTTATGACTATTC 1791 4731_A22S26

TABLE 3 KRAS duplexes with modified sequences Seq Seq SEQ SEQ Sense IDID Duplex Sequence NO: Anti sense Sequence NO: AD-35523.3GGAcGAAuAuGAuccAAcAdTdT 855 UGUUGGAUcAuAUUCGUCCdTdT 1282 AD-35529.1GAcGAAuAuGAuccAAcAAdTdT 856 UUGUUGGAUcAuAUUCGUCdTdT 1283 AD-35535.4AcGAAuAuGAuccAAcAAudTdT 857 AUUGUUGGAUcAuAUUCGUdTdT 1284 AD-35541.4cGAAuAuGAuccAAcAAuAdTdT 858 uAUUGUUGGAUcAuAUUCGdTdT 1285 AD-35547.4GAAuAuGAuccAAcAAuAGdTdT 859 CuAUUGUUGGAUcAuAUUCdTdT 1286 AD-35553.4AAuAuGAuccAAcAAuAGAdTdT 860 UCuAUUGUUGGAUcAuAUUdTdT 1287 AD-35559.4AuAuGAuccAAcAAuAGAGdTdT 861 CUCuAUUGUUGGAUcAuAUdTdT 1288 AD-35565.4uAuGAuccAAcAAuAGAGGdTdT 862 CCUCuAUUGUUGGAUcAuAdTdT 1289 AD-35524.4AuGAuccAAcAAuAGAGGAdTdT 863 UCCUCuAUUGUUGGAUcAUdTdT 1290 AD-35530.4uGAuccAAcAAuAGAGGAudTdT 864 AUCCUCuAUUGUUGGAUcAdTdT 1291 AD-35536.4GAuccAAcAAuAGAGGAuudTdT 865 AAUCCUCuAUUGUUGGAUCdTdT 1292 AD-35542.4AuccAAcAAuAGAGGAuucdTdT 866 GAAUCCUCuAUUGUUGGAUdTdT 1293 AD-35548.4uccAAcAAuAGAGGAuuccdTdT 867 GGAAUCCUCuAUUGUUGGAdTdT 1294 AD-35554.4ccAAcAAuAGAGGAuuccudTdT 868 AGGAAUCCUCuAUUGUUGGdTdT 1295 AD-35560.2cAAcAAuAGAGGAuuccuAdTdT 869 uAGGAAUCCUCuAUUGUUGdTdT 1296 AD-35566.4AAcAAuAGAGGAuuccuAcdTdT 870 GuAGGAAUCCUCuAUUGUUdTdT 1297 AD-35525.2AcAAuAGAGGAuuccuAcAdTdT 871 UGuAGGAAUCCUCuAUUGUdTdT 1298 AD-35531.4cAAuAGAGGAuuccuAcAGdTdT 872 CUGuAGGAAUCCUCuAUUGdTdT 1299 AD-35537.4AAuAGAGGAuuccuAcAGGdTdT 873 CCUGuAGGAAUCCUCuAUUdTdT 1300 AD-35543.2AuAGAGGAuuccuAcAGGAdTdT 874 UCCUGuAGGAAUCCUCuAUdTdT 1301 AD-35549.4uAGAGGAuuccuAcAGGAAdTdT 875 UUCCUGuAGGAAUCCUCuAdTdT 1302 AD-35555.4AGAGGAuuccuAcAGGAAGdTdT 876 CUUCCUGuAGGAAUCCUCUdTdT 1303 AD-35561.4GAGGAuuccuAcAGGAAGcdTdT 877 GCUUCCUGuAGGAAUCCUCdTdT 1304 AD-35567.4AGGAuuccuAcAGGAAGcAdTdT 878 UGCUUCCUGuAGGAAUCCUdTdT 1305 AD-35526.4GGAuuccuAcAGGAAGcAAdTdT 879 UUGCUUCCUGuAGGAAUCCdTdT 1306 AD-35532.4GAuuccuAcAGGAAGcAAGdTdT 880 CUUGCUUCCUGuAGGAAUCdTdT 1307 AD-35538.4AuuccuAcAGGAAGcAAGudTdT 881 ACUUGCUUCCUGuAGGAAUdTdT 1308 AD-35544.4uuccuAcAGGAAGcAAGuAdTdT 882 uACUUGCUUCCUGuAGGAAdTdT 1309 AD-35550.4uccuAcAGGAAGcAAGuAGdTdT 883 CuACUUGCUUCCUGuAGGAdTdT 1310 AD-35556.4ccuAcAGGAAGcAAGuAGudTdT 884 ACuACUUGCUUCCUGuAGGdTdT 1311 AD-35562.4cuAcAGGAAGcAAGuAGuAdTdT 885 uACuACUUGCUUCCUGuAGdTdT 1312 AD-35568.4uAcAGGAAGcAAGuAGuAAdTdT 886 UuACuACUUGCUUCCUGuAdTdT 1313 AD-35527.4AcAGGAAGcAAGuAGuAAudTdT 887 AUuACuACUUGCUUCCUGUdTdT 1314 AD-35533.4cAGGAAGcAAGuAGuAAuudTdT 888 AAUuACuACUUGCUUCCUGdTdT 1315 AD-35539.4uuGGAuAuucucGAcAcAGdTdT 889 CUGUGUCGAGAAuAUCcAAdTdT 1316 AD-35545.4uGGAuAuucucGAcAcAGcdTdT 890 GCUGUGUCGAGAAuAUCcAdTdT 1317 AD-35551.4GGAuAuucucGAcAcAGcAdTdT 891 UGCUGUGUCGAGAAuAUCCdTdT 1318 AD-35563.4AuAuucucGAcAcAGcAGGdTdT 892 CCUGCUGUGUCGAGAAuAUdTdT 1319 AD-35528.4AuucucGAcAcAGcAGGucdTdT 893 GACCUGCUGUGUCGAGAAUdTdT 1320 AD-35540.4ucucGAcAcAGcAGGucAAdTdT 894 UUGACCUGCUGUGUCGAGAdTdT 1321 AD-35546.4cucGAcAcAGcAGGucAAGdTdT 895 CUUGACCUGCUGUGUCGAGdTdT 1322 AD-35552.4ucGAcAcAGcAGGucAAGAdTdT 896 UCUUGACCUGCUGUGUCGAdTdT 1323 AD-35558.4cGAcAcAGcAGGucAAGAGdTdT 897 CUCUUGACCUGCUGUGUCGdTdT 1324 AD-35564.4GAcAcAGcAGGucAAGAGGdTdT 898 CCUCUUGACCUGCUGUGUCdTdT 1325 AD-35570.4AcAcAGcAGGucAAGAGGAdTdT 899 UCCUCUUGACCUGCUGUGUdTdT 1326 AD-35571.4cAcAGcAGGucAAGAGGAGdTdT 900 CUCCUCUUGACCUGCUGUGdTdT 1327 AD-35577.4AcAGcAGGucAAGAGGAGudTdT 901 ACUCCUCUUGACCUGCUGUdTdT 1328 AD-35583.4cAGcAGGucAAGAGGAGuAdTdT 902 uACUCCUCUUGACCUGCUGdTdT 1329 AD-35589.4AGcAGGucAAGAGGAGuAcdTdT 903 GuACUCCUCUUGACCUGCUdTdT 1330 AD-35595.4GcAGGucAAGAGGAGuAcAdTdT 904 UGuACUCCUCUUGACCUGCdTdT 1331 AD-35601.4cAGGucAAGAGGAGuAcAGdTdT 905 CUGuACUCCUCUUGACCUGdTdT 1332 AD-35607.4AGGucAAGAGGAGuAcAGudTdT 906 ACUGuACUCCUCUUGACCUdTdT 1333 AD-35613.4GGucAAGAGGAGuAcAGuGdTdT 907 cACUGuACUCCUCUUGACCdTdT 1334 AD-35572.4GucAAGAGGAGuAcAGuGcdTdT 908 GcACUGuACUCCUCUUGACdTdT 1335 AD-35578.4ucAAGAGGAGuAcAGuGcAdTdT 909 UGcACUGuACUCCUCUUGAdTdT 1336 AD-35584.4cAAGAGGAGuAcAGuGcAAdTdT 910 UUGcACUGuACUCCUCUUGdTdT 1337 AD-35590.4AAGAGGAGuAcAGuGcAAudTdT 911 AUUGcACUGuACUCCUCUUdTdT 1338 AD-35596.4AGAGGAGuAcAGuGcAAuGdTdT 912 cAUUGcACUGuACUCCUCUdTdT 1339 AD-35602.4GAGGAGuAcAGuGcAAuGAdTdT 913 UcAUUGcACUGuACUCCUCdTdT 1340 AD-35608.4AGGAGuAcAGuGcAAuGAGdTdT 914 CUcAUUGcACUGuACUCCUdTdT 1341 AD-35614.4GGAGuAcAGuGcAAuGAGGdTdT 915 CCUcAUUGcACUGuACUCCdTdT 1342 AD-35573.4GAGuAcAGuGcAAuGAGGGdTdT 916 CCCUcAUUGcACUGuACUCdTdT 1343 AD-35579.4GGGGAGGGcuuucuuuGuGdTdT 917 cAcAAAGAAAGCCCUCCCCdTdT 1344 AD-35585.4GGGAGGGcuuucuuuGuGudTdT 918 AcAcAAAGAAAGCCCUCCCdTdT 1345 AD-35591.4GGAGGGcuuucuuuGuGuAdTdT 919 uAcAcAAAGAAAGCCCUCCdTdT 1346 AD-35597.4GAGGGcuuucuuuGuGuAudTdT 920 AuAcAcAAAGAAAGCCCUCdTdT 1347 AD-35603.4AGGGcuuucuuuGuGuAuudTdT 921 AAuAcAcAAAGAAAGCCCUdTdT 1348 AD-35609.4GGGcuuucuuuGuGuAuuudTdT 922 AAAuAcAcAAAGAAAGCCCdTdT 1349 AD-35615.4GGcuuucuuuGuGuAuuuGdTdT 923 cAAAuAcAcAAAGAAAGCCdTdT 1350 AD-35574.4GcuuucuuuGuGuAuuuGcdTdT 924 GcAAAuAcAcAAAGAAAGCdTdT 1351 AD-35580.1cuuucuuuGuGuAuuuGccdTdT 925 GGcAAAuAcAcAAAGAAAGdTdT 1352 AD-35586.4uuucuuuGuGuAuuuGccAdTdT 926 UGGcAAAuAcAcAAAGAAAdTdT 1353 AD-35592.4uucuuuGuGuAuuuGccAudTdT 927 AUGGcAAAuAcAcAAAGAAdTdT 1354 AD-35598.4ucuuuGuGuAuuuGccAuAdTdT 928 uAUGGcAAAuAcAcAAAGAdTdT 1355 AD-35604.4cuuuGuGuAuuuGccAuAAdTdT 929 UuAUGGcAAAuAcAcAAAGdTdT 1356 AD-35610.4uuuGuGuAuuuGccAuAAAdTdT 930 UUuAUGGcAAAuAcAcAAAdTdT 1357 AD-35616.4uuGuGuAuuuGccAuAAAudTdT 931 AUUuAUGGcAAAuAcAcAAdTdT 1358 AD-35575.4uGuGuAuuuGccAuAAAuAdTdT 932 uAUUuAUGGcAAAuAcAcAdTdT 1359 AD-35581.4GuGuAuuuGccAuAAAuAAdTdT 933 UuAUUuAUGGcAAAuAcACdTdT 1360 AD-35587.4uGuAuuuGccAuAAAuAAudTdT 934 AUuAUUuAUGGcAAAuAcAdTdT 1361 AD-35593.4GuAuuuGccAuAAAuAAuAdTdT 935 uAUuAUUuAUGGcAAAuACdTdT 1362 AD-35599.4uAuuuGccAuAAAuAAuAcdTdT 936 GuAUuAUUuAUGGcAAAuAdTdT 1363 AD-35605.4AuuuGccAuAAAuAAuAcudTdT 937 AGuAUuAUUuAUGGcAAAUdTdT 1364 AD-35611.4uuuGccAuAAAuAAuAcuAdTdT 938 uAGuAUuAUUuAUGGcAAAdTdT 1365 AD-35617.4uGAAGAuAuucAccAuuAudTdT 939 AuAAUGGUGAAuAUCUUcAdTdT 1366 AD-35576.4GAAGAuAuucAccAuuAuAdTdT 940 uAuAAUGGUGAAuAUCUUCdTdT 1367 AD-35588.4AGAuAuucAccAuuAuAGAdTdT 941 UCuAuAAUGGUGAAuAUCUdTdT 1368 AD-35667.1AAAcAucAGcAAAGAcAAGdTdT 942 CUUGUCUUUGCUGAUGUUUdTdT 1369 AD-35673.1AAcAucAGcAAAGAcAAGAdTdT 943 UCUUGUCUUUGCUGAUGUUdTdT 1370 AD-35679.1AcAucAGcAAAGAcAAGAcdTdT 944 GUCUUGUCUUUGCUGAUGUdTdT 1371 AD-35685.1cAucAGcAAAGAcAAGAcAdTdT 945 UGUCUUGUCUUUGCUGAUGdTdT 1372 AD-35691.1AucAGcAAAGAcAAGAcAGdTdT 946 CUGUCUUGUCUUUGCUGAUdTdT 1373 AD-35557.1GAuAuucucGAcAcAGcAGdTdT 947 CUGCUGUGUCGAGAAuAUCdTdT 1374 AD-35618.1uucAccAuuAuAGAGAAcAdTdT 948 UGUUCUCuAuAAUGGUGAAdTdT 1375 AD-35569.1uAuucucGAcAcAGcAGGudTdT 949 ACCUGCUGUGUCGAGAAuAdTdT 1376 AD-35534.1uucucGAcAcAGcAGGucAdTdT 950 UGACCUGCUGUGUCGAGAAdTdT 1377 AD-35582.1AAGAuAuucAccAuuAuAGdTdT 951 CuAuAAUGGUGAAuAUCUUdTdT 1378 AD-35594.1GAuAuucAccAuuAuAGAGdTdT 952 CUCuAuAAUGGUGAAuAUCdTdT 1379 AD-35600.1AuAuucAccAuuAuAGAGAdTdT 953 UCUCuAuAAUGGUGAAuAUdTdT 1380 AD-35606.1uAuucAccAuuAuAGAGAAdTdT 954 UUCUCuAuAAUGGUGAAuAdTdT 1381 AD-35612.1AuucAccAuuAuAGAGAAcdTdT 955 GUUCUCuAuAAUGGUGAAUdTdT 1382 AD-38127.1ucAccAuuAuAGAGAAcAAdTdT 956 UUGUUCUCuAuAAUGGUGAdTdT 1383 AD-38133.1cAccAuuAuAGAGAAcAAAdTdT 957 UUUGUUCUCuAuAAUGGUGdTdT 1384 AD-38139.1AccAuuAuAGAGAAcAAAudTdT 958 AUUUGUUCUCuAuAAUGGUdTdT 1385 AD-38145.1ccAuuAuAGAGAAcAAAuudTdT 959 AAUUUGUUCUCuAuAAUGGdTdT 1386 AD-38151.1cAuuAuAGAGAAcAAAuuAdTdT 960 uAAUUUGUUCUCuAuAAUGdTdT 1387 AD-38157.1AuuAuAGAGAAcAAAuuAAdTdT 961 UuAAUUUGUUCUCuAuAAUdTdT 1388 AD-38163.1uuAuAGAGAAcAAAuuAAAdTdT 962 UUuAAUUUGUUCUCuAuAAdTdT 1389 AD-38169.1uAuAGAGAAcAAAuuAAAAdTdT 963 UUUuAAUUUGUUCUCuAuAdTdT 1390 AD-38128.1AuAGAGAAcAAAuuAAAAGdTdT 964 CUUUuAAUUUGUUCUCuAUdTdT 1391 AD-38134.1uAGAGAAcAAAuuAAAAGAdTdT 965 UCUUUuAAUUUGUUCUCuAdTdT 1392 AD-38140.1AGAGAAcAAAuuAAAAGAGdTdT 966 CUCUUUuAAUUUGUUCUCUdTdT 1393 AD-38146.1GAAGAuGuAccuAuGGuccdTdT 967 GGACcAuAGGuAcAUCUUCdTdT 1394 AD-38152.1AAGAuGuAccuAuGGuccudTdT 968 AGGACcAuAGGuAcAUCUUdTdT 1395 AD-38158.1AGAuGuAccuAuGGuccuAdTdT 969 uAGGACcAuAGGuAcAUCUdTdT 1396 AD-38164.1GAuGuAccuAuGGuccuAGdTdT 970 CuAGGACcAuAGGuAcAUCdTdT 1397 AD-38170.1AuGuAccuAuGGuccuAGudTdT 971 ACuAGGACcAuAGGuAcAUdTdT 1398 AD-38129.1uGuAccuAuGGuccuAGuAdTdT 972 uACuAGGACcAuAGGuAcAdTdT 1399 AD-38135.1GuAccuAuGGuccuAGuAGdTdT 973 CuACuAGGACcAuAGGuACdTdT 1400 AD-38141.1uAccuAuGGuccuAGuAGGdTdT 974 CCuACuAGGACcAuAGGuAdTdT 1401 AD-38147.1AccuAuGGuccuAGuAGGAdTdT 975 UCCuACuAGGACcAuAGGUdTdT 1402 AD-38153.1ccuAuGGuccuAGuAGGAAdTdT 976 UUCCuACuAGGACcAuAGGdTdT 1403 AD-38159.1cuAuGGuccuAGuAGGAAAdTdT 977 UUUCCuACuAGGACcAuAGdTdT 1404 AD-38165.1uAuGGuccuAGuAGGAAAudTdT 978 AUUUCCuACuAGGACcAuAdTdT 1405 AD-38171.1AuGGuccuAGuAGGAAAuAdTdT 979 uAUUUCCuACuAGGACcAUdTdT 1406 AD-38130.1uGGuccuAGuAGGAAAuAAdTdT 980 UuAUUUCCuACuAGGACcAdTdT 1407 AD-38136.1GGuccuAGuAGGAAAuAAAdTdT 981 UUuAUUUCCuACuAGGACCdTdT 1408 AD-38142.1GuccuAGuAGGAAAuAAAudTdT 982 AUUuAUUUCCuACuAGGACdTdT 1409 AD-38148.1uccuAGuAGGAAAuAAAuGdTdT 983 cAUUuAUUUCCuACuAGGAdTdT 1410 AD-38154.1ccuAGuAGGAAAuAAAuGudTdT 984 AcAUUuAUUUCCuACuAGGdTdT 1411 AD-38160.1cuAGuAGGAAAuAAAuGuGdTdT 985 cAcAUUuAUUUCCuACuAGdTdT 1412 AD-38166.1uAGuAGGAAAuAAAuGuGAdTdT 986 UcAcAUUuAUUUCCuACuAdTdT 1413 AD-38172.1AGuAGGAAAuAAAuGuGAudTdT 987 AUcAcAUUuAUUUCCuACUdTdT 1414 AD-38131.1GGAAuuccuuuuAuuGAAAdTdT 988 UUUcAAuAAAAGGAAUUCCdTdT 1415 AD-38137.1GAAuuccuuuuAuuGAAAcdTdT 989 GUUUcAAuAAAAGGAAUUCdTdT 1416 AD-38143.1AAuuccuuuuAuuGAAAcAdTdT 990 UGUUUcAAuAAAAGGAAUUdTdT 1417 AD-38149.1AuuccuuuuAuuGAAAcAudTdT 991 AUGUUUcAAuAAAAGGAAUdTdT 1418 AD-38155.1uuccuuuuAuuGAAAcAucdTdT 992 GAUGUUUcAAuAAAAGGAAdTdT 1419 AD-38161.1uccuuuuAuuGAAAcAucAdTdT 993 UGAUGUUUcAAuAAAAGGAdTdT 1420 AD-38167.1ccuuuuAuuGAAAcAucAGdTdT 994 CUGAUGUUUcAAuAAAAGGdTdT 1421 AD-38173.1cuuuuAuuGAAAcAucAGcdTdT 995 GCUGAUGUUUcAAuAAAAGdTdT 1422 AD-38132.1uuuuAuuGAAAcAucAGcAdTdT 996 UGCUGAUGUUUcAAuAAAAdTdT 1423 AD-38138.1uuuAuuGAAAcAucAGcAAdTdT 997 UUGCUGAUGUUUcAAuAAAdTdT 1424 AD-38144.1uuAuuGAAAcAucAGcAAAdTdT 998 UUUGCUGAUGUUUcAAuAAdTdT 1425 AD-38150.1uAuuGAAAcAucAGcAAAGdTdT 999 CUUUGCUGAUGUUUcAAuAdTdT 1426 AD-38156.1AuuGAAAcAucAGcAAAGAdTdT 1000 UCUUUGCUGAUGUUUcAAUdTdT 1427 AD-38162.1uuGAAAcAucAGcAAAGAcdTdT 1001 GUCUUUGCUGAUGUUUcAAdTdT 1428 AD-38168.1uGAAAcAucAGcAAAGAcAdTdT 1002 UGUCUUUGCUGAUGUUUcAdTdT 1429 AD-38174.1GAAAcAucAGcAAAGAcAAdTdT 1003 UUGUCUUUGCUGAUGUUUCdTdT 1430 AD-39683.1AuGAcuGAAuAuAAAcuuGdTdT 1004 cAAGUUuAuAUUcAGUcAUdTdT 1431 AD-39689.1uGAcuGAAuAuAAAcuuGudTdT 1005 AcAAGUUuAuAUUcAGUcAdTdT 1432 AD-39695.1GAcuGAAuAuAAAcuuGuGdTdT 1006 cAcAAGUUuAuAUUcAGUCdTdT 1433 AD-39701.1AcuGAAuAuAAAcuuGuGGdTdT 1007 CcAcAAGUUuAuAUUcAGUdTdT 1434 AD-39707.1cuGAAuAuAAAcuuGuGGudTdT 1008 ACcAcAAGUUuAuAUUcAGdTdT 1435 AD-39713.1uGAAuAuAAAcuuGuGGuAdTdT 1009 uACcAcAAGUUuAuAUUcAdTdT 1436 AD-39719.1GAAuAuAAAcuuGuGGuAGdTdT 1010 CuACcAcAAGUUuAuAUUCdTdT 1437 AD-39725.1AAuAuAAAcuuGuGGuAGudTdT 1011 ACuACcAcAAGUUuAuAUUdTdT 1438 AD-39684.1AuAuAAAcuuGuGGuAGuudTdT 1012 AACuACcAcAAGUUuAuAUdTdT 1439 AD-39690.1uAuAAAcuuGuGGuAGuuGdTdT 1013 cAACuACcAcAAGUUuAuAdTdT 1440 AD-39696.1AuAAAcuuGuGGuAGuuGGdTdT 1014 CcAACuACcAcAAGUUuAUdTdT 1441 AD-39702.1uAAAcuuGuGGuAGuuGGAdTdT 1015 UCcAACuACcAcAAGUUuAdTdT 1442 AD-39708.1AAAcuuGuGGuAGuuGGAGdTdT 1016 CUCcAACuACcAcAAGUUUdTdT 1443 AD-39714.1AAcuuGuGGuAGuuGGAGcdTdT 1017 GCUCcAACuACcAcAAGUUdTdT 1444 AD-39720.1AcuuGuGGuAGuuGGAGcudTdT 1018 AGCUCcAACuACcAcAAGUdTdT 1445 AD-39726.1cuuGuGGuAGuuGGAGcuGdTdT 1019 cAGCUCcAACuACcAcAAGdTdT 1446 AD-39685.1uuGuGGuAGuuGGAGcuGGdTdT 1020 CcAGCUCcAACuACcAcAAdTdT 1447 AD-39691.1uGuGGuAGuuGGAGcuGGudTdT 1021 ACcAGCUCcAACuACcAcAdTdT 1448 AD-39697.1GuGGuAGuuGGAGcuGGuGdTdT 1022 cACcAGCUCcAACuACcACdTdT 1449 AD-39703.1uGGuAGuuGGAGcuGGuGGdTdT 1023 CcACcAGCUCcAACuACcAdTdT 1450 AD-39709.1GGuAGuuGGAGcuGGuGGcdTdT 1024 GCcACcAGCUCcAACuACCdTdT 1451 AD-39715.1GuAGuuGGAGcuGGuGGcGdTdT 1025 CGCcACcAGCUCcAACuACdTdT 1452 AD-39721.1uAGuuGGAGcuGGuGGcGudTdT 1026 ACGCcACcAGCUCcAACuAdTdT 1453 AD-39727.1AGuuGGAGcuGGuGGcGuAdTdT 1027 uACGCcACcAGCUCcAACUdTdT 1454 AD-39686.1GuuGGAGcuGGuGGcGuAGdTdT 1028 CuACGCcACcAGCUCcAACdTdT 1455 AD-39692.1uuGGAGcuGGuGGcGuAGGdTdT 1029 CCuACGCcACcAGCUCcAAdTdT 1456 AD-39698.1uGGAGcuGGuGGcGuAGGcdTdT 1030 GCCuACGCcACcAGCUCcAdTdT 1457 AD-39704.1GGAGcuGGuGGcGuAGGcAdTdT 1031 UGCCuACGCcACcAGCUCCdTdT 1458 AD-39710.1GAGcuGGuGGcGuAGGcAAdTdT 1032 UUGCCuACGCcACcAGCUCdTdT 1459 AD-39716.1AGcuGGuGGcGuAGGcAAGdTdT 1033 CUUGCCuACGCcACcAGCUdTdT 1460 AD-39722.1GcuGGuGGcGuAGGcAAGAdTdT 1034 UCUUGCCuACGCcACcAGCdTdT 1461 AD-39728.1cuGGuGGcGuAGGcAAGAGdTdT 1035 CUCUUGCCuACGCcACcAGdTdT 1462 AD-39687.1uGGuGGcGuAGGcAAGAGudTdT 1036 ACUCUUGCCuACGCcACcAdTdT 1463 AD-39693.1GGuGGcGuAGGcAAGAGuGdTdT 1037 cACUCUUGCCuACGCcACCdTdT 1464 AD-39699.1GuGGcGuAGGcAAGAGuGcdTdT 1038 GcACUCUUGCCuACGCcACdTdT 1465 AD-39705.1uGGcGuAGGcAAGAGuGccdTdT 1039 GGcACUCUUGCCuACGCcAdTdT 1466 AD-39711.1GGcGuAGGcAAGAGuGccudTdT 1040 AGGcACUCUUGCCuACGCCdTdT 1467 AD-39717.1GcGuAGGcAAGAGuGccuudTdT 1041 AAGGcACUCUUGCCuACGCdTdT 1468 AD-39723.1cGuAGGcAAGAGuGccuuGdTdT 1042 cAAGGcACUCUUGCCuACGdTdT 1469 AD-39729.1GuAGGcAAGAGuGccuuGAdTdT 1043 UcAAGGcACUCUUGCCuACdTdT 1470 AD-39688.1uAGGcAAGAGuGccuuGAcdTdT 1044 GUcAAGGcACUCUUGCCuAdTdT 1471 AD-39694.1AGGcAAGAGuGccuuGAcGdTdT 1045 CGUcAAGGcACUCUUGCCUdTdT 1472 AD-39700.1GGcAAGAGuGccuuGAcGAdTdT 1046 UCGUcAAGGcACUCUUGCCdTdT 1473 AD-39706.1GcAAGAGuGccuuGAcGAudTdT 1047 AUCGUcAAGGcACUCUUGCdTdT 1474 AD-39712.1cAAGAGuGccuuGAcGAuAdTdT 1048 uAUCGUcAAGGcACUCUUGdTdT 1475 AD-39718.1AAGAGuGccuuGAcGAuAcdTdT 1049 GuAUCGUcAAGGcACUCUUdTdT 1476 AD-39724.1AGAGuGccuuGAcGAuAcAdTdT 1050 UGuAUCGUcAAGGcACUCUdTdT 1477 AD-39730.1GAGuGccuuGAcGAuAcAGdTdT 1051 CUGuAUCGUcAAGGcACUCdTdT 1478 AD-39736.1AGuGccuuGAcGAuAcAGcdTdT 1052 GCUGuAUCGUcAAGGcACUdTdT 1479 AD-39742.1GuGccuuGAcGAuAcAGcudTdT 1053 AGCUGuAUCGUcAAGGcACdTdT 1480 AD-39748.1uGccuuGAcGAuAcAGcuAdTdT 1054 uAGCUGuAUCGUcAAGGcAdTdT 1481 AD-39754.1GccuuGAcGAuAcAGcuAAdTdT 1055 UuAGCUGuAUCGUcAAGGCdTdT 1482 AD-39760.1ccuuGAcGAuAcAGcuAAudTdT 1056 AUuAGCUGuAUCGUcAAGGdTdT 1483 AD-39766.1cuuGAcGAuAcAGcuAAuudTdT 1057 AAUuAGCUGuAUCGUcAAGdTdT 1484 AD-39772.1uuGAcGAuAcAGcuAAuucdTdT 1058 GAAUuAGCUGuAUCGUcAAdTdT 1485 AD-39731.1uGAcGAuAcAGcuAAuucAdTdT 1059 UGAAUuAGCUGuAUCGUcAdTdT 1486 AD-39737.1GAcGAuAcAGcuAAuucAGdTdT 1060 CUGAAUuAGCUGuAUCGUCdTdT 1487 AD-39743.1AcGAuAcAGcuAAuucAGAdTdT 1061 UCUGAAUuAGCUGuAUCGUdTdT 1488 AD-39749.1cGAuAcAGcuAAuucAGAAdTdT 1062 UUCUGAAUuAGCUGuAUCGdTdT 1489 AD-39755.1GAuAcAGcuAAuucAGAAudTdT 1063 AUUCUGAAUuAGCUGuAUCdTdT 1490 AD-39761.1AuAcAGcuAAuucAGAAucdTdT 1064 GAUUCUGAAUuAGCUGuAUdTdT 1491 AD-39767.1uAcAGcuAAuucAGAAucAdTdT 1065 UGAUUCUGAAUuAGCUGuAdTdT 1492 AD-39773.1AcAGcuAAuucAGAAucAudTdT 1066 AUGAUUCUGAAUuAGCUGUdTdT 1493 AD-39732.1cAGcuAAuucAGAAucAuudTdT 1067 AAUGAUUCUGAAUuAGCUGdTdT 1494 AD-39738.1AGcuAAuucAGAAucAuuudTdT 1068 AAAUGAUUCUGAAUuAGCUdTdT 1495 AD-39744.1GcuAAuucAGAAucAuuuudTdT 1069 AAAAUGAUUCUGAAUuAGCdTdT 1496 AD-39750.1cuAAuucAGAAucAuuuuGdTdT 1070 cAAAAUGAUUCUGAAUuAGdTdT 1497 AD-39756.1uAAuucAGAAucAuuuuGudTdT 1071 AcAAAAUGAUUCUGAAUuAdTdT 1498 AD-39762.1AAuucAGAAucAuuuuGuGdTdT 1072 cAcAAAAUGAUUCUGAAUUdTdT 1499 AD-39768.1AuucAGAAucAuuuuGuGGdTdT 1073 CcAcAAAAUGAUUCUGAAUdTdT 1500 AD-39774.1uucAGAAucAuuuuGuGGAdTdT 1074 UCcAcAAAAUGAUUCUGAAdTdT 1501 AD-39733.1ucAGAAucAuuuuGuGGAcdTdT 1075 GUCcAcAAAAUGAUUCUGAdTdT 1502 AD-39739.1cAGAAucAuuuuGuGGAcGdTdT 1076 CGUCcAcAAAAUGAUUCUGdTdT 1503 AD-39745.1AGAAucAuuuuGuGGAcGAdTdT 1077 UCGUCcAcAAAAUGAUUCUdTdT 1504 AD-39751.1GAAucAuuuuGuGGAcGAAdTdT 1078 UUCGUCcAcAAAAUGAUUCdTdT 1505 AD-39757.1AAucAuuuuGuGGAcGAAudTdT 1079 AUUCGUCcAcAAAAUGAUUdTdT 1506 AD-39763.1AucAuuuuGuGGAcGAAuAdTdT 1080 uAUUCGUCcAcAAAAUGAUdTdT 1507 AD-39769.1ucAuuuuGuGGAcGAAuAudTdT 1081 AuAUUCGUCcAcAAAAUGAdTdT 1508 AD-39775.1cAuuuuGuGGAcGAAuAuGdTdT 1082 cAuAUUCGUCcAcAAAAUGdTdT 1509 AD-39734.1AuuuuGuGGAcGAAuAuGAdTdT 1083 UcAuAUUCGUCcAcAAAAUdTdT 1510 AD-39740.1uuuuGuGGAcGAAuAuGAudTdT 1084 AUcAuAUUCGUCcAcAAAAdTdT 1511 AD-39746.1uuuGuGGAcGAAuAuGAucdTdT 1085 GAUcAuAUUCGUCcAcAAAdTdT 1512 AD-39752.1uuGuGGAcGAAuAuGAuccdTdT 1086 GGAUcAuAUUCGUCcAcAAdTdT 1513 AD-39758.1uGuGGAcGAAuAuGAuccAdTdT 1087 UGGAUcAuAUUCGUCcAcAdTdT 1514 AD-39764.1GuGGAcGAAuAuGAuccAAdTdT 1088 UUGGAUcAuAUUCGUCcACdTdT 1515 AD-39770.1uGGAcGAAuAuGAuccAAcdTdT 1089 GUUGGAUcAuAUUCGUCcAdTdT 1516 AD-39776.1AGGAAGcAAGuAGuAAuuGdTdT 1090 cAAUuACuACUUGCUUCCUdTdT 1517 AD-39735.1GGAAGcAAGuAGuAAuuGAdTdT 1091 UcAAUuACuACUUGCUUCCdTdT 1518 AD-39741.1GAAGcAAGuAGuAAuuGAudTdT 1092 AUcAAUuACuACUUGCUUCdTdT 1519 AD-39747.1AAGcAAGuAGuAAuuGAuGdTdT 1093 cAUcAAUuACuACUUGCUUdTdT 1520 AD-39753.1AGcAAGuAGuAAuuGAuGGdTdT 1094 CcAUcAAUuACuACUUGCUdTdT 1521 AD-39759.1GcAAGuAGuAAuuGAuGGAdTdT 1095 UCcAUcAAUuACuACUUGCdTdT 1522 AD-39765.1cAAGuAGuAAuuGAuGGAGdTdT 1096 CUCcAUcAAUuACuACUUGdTdT 1523 AD-39771.1AAGuAGuAAuuGAuGGAGAdTdT 1097 UCUCcAUcAAUuACuACUUdTdT 1524 AD-39778.1AGuAGuAAuuGAuGGAGAAdTdT 1098 UUCUCcAUcAAUuACuACUdTdT 1525 AD-39784.1GuAGuAAuuGAuGGAGAAAdTdT 1099 UUUCUCcAUcAAUuACuACdTdT 1526 AD-39790.1uAGuAAuuGAuGGAGAAAcdTdT 1100 GUUUCUCcAUcAAUuACuAdTdT 1527 AD-39796.1AGuAAuuGAuGGAGAAAccdTdT 1101 GGUUUCUCcAUcAAUuACUdTdT 1528 AD-39802.1GuAAuuGAuGGAGAAAccudTdT 1102 AGGUUUCUCcAUcAAUuACdTdT 1529 AD-39808.1uAAuuGAuGGAGAAAccuGdTdT 1103 cAGGUUUCUCcAUcAAUuAdTdT 1530 AD-39814.1AAuuGAuGGAGAAAccuGudTdT 1104 AcAGGUUUCUCcAUcAAUUdTdT 1531 AD-39820.1AuuGAuGGAGAAAccuGucdTdT 1105 GAcAGGUUUCUCcAUcAAUdTdT 1532 AD-39779.1uuGAuGGAGAAAccuGucudTdT 1106 AGAcAGGUUUCUCcAUcAAdTdT 1533 AD-39785.1uGAuGGAGAAAccuGucucdTdT 1107 GAGAcAGGUUUCUCcAUcAdTdT 1534 AD-39791.1GAuGGAGAAAccuGucucudTdT 1108 AGAGAcAGGUUUCUCcAUCdTdT 1535 AD-39797.1AuGGAGAAAccuGucucuudTdT 1109 AAGAGAcAGGUUUCUCcAUdTdT 1536 AD-39803.1uGGAGAAAccuGucucuuGdTdT 1110 cAAGAGAcAGGUUUCUCcAdTdT 1537 AD-39809.1GGAGAAAccuGucucuuGGdTdT 1111 CcAAGAGAcAGGUUUCUCCdTdT 1538 AD-39815.1GAGAAAccuGucucuuGGAdTdT 1112 UCcAAGAGAcAGGUUUCUCdTdT 1539 AD-39821.1AGAAAccuGucucuuGGAudTdT 1113 AUCcAAGAGAcAGGUUUCUdTdT 1540 AD-39780.1GAAAccuGucucuuGGAuAdTdT 1114 uAUCcAAGAGAcAGGUUUCdTdT 1541 AD-39786.1AAAccuGucucuuGGAuAudTdT 1115 AuAUCcAAGAGAcAGGUUUdTdT 1542 AD-39792.1AAccuGucucuuGGAuAuudTdT 1116 AAuAUCcAAGAGAcAGGUUdTdT 1543 AD-39798.1AccuGucucuuGGAuAuucdTdT 1117 GAAuAUCcAAGAGAcAGGUdTdT 1544 AD-39804.1ccuGucucuuGGAuAuucudTdT 1118 AGAAuAUCcAAGAGAcAGGdTdT 1545 AD-39810.1cuGucucuuGGAuAuucucdTdT 1119 GAGAAuAUCcAAGAGAcAGdTdT 1546 AD-39816.1uGucucuuGGAuAuucucGdTdT 1120 CGAGAAuAUCcAAGAGAcAdTdT 1547 AD-39822.1GucucuuGGAuAuucucGAdTdT 1121 UCGAGAAuAUCcAAGAGACdTdT 1548 AD-39781.1ucucuuGGAuAuucucGAcdTdT 1122 GUCGAGAAuAUCcAAGAGAdTdT 1549 AD-39787.1cucuuGGAuAuucucGAcAdTdT 1123 UGUCGAGAAuAUCcAAGAGdTdT 1550 AD-39793.1ucuuGGAuAuucucGAcAcdTdT 1124 GUGUCGAGAAuAUCcAAGAdTdT 1551 AD-39799.1cuuGGAuAuucucGAcAcAdTdT 1125 UGUGUCGAGAAuAUCcAAGdTdT 1552 AD-39805.1AGuAcAGuGcAAuGAGGGAdTdT 1126 UCCCUcAUUGcACUGuACUdTdT 1553 AD-39811.1GuAcAGuGcAAuGAGGGAcdTdT 1127 GUCCCUcAUUGcACUGuACdTdT 1554 AD-39817.1uAcAGuGcAAuGAGGGAccdTdT 1128 GGUCCCUcAUUGcACUGuAdTdT 1555 AD-39823.1AcAGuGcAAuGAGGGAccAdTdT 1129 UGGUCCCUcAUUGcACUGUdTdT 1556 AD-39782.1cAGuGcAAuGAGGGAccAGdTdT 1130 CUGGUCCCUcAUUGcACUGdTdT 1557 AD-39788.1AGuGcAAuGAGGGAccAGudTdT 1131 ACUGGUCCCUcAUUGcACUdTdT 1558 AD-39794.1GuGcAAuGAGGGAccAGuAdTdT 1132 uACUGGUCCCUcAUUGcACdTdT 1559 AD-39800.1uGcAAuGAGGGAccAGuAcdTdT 1133 GuACUGGUCCCUcAUUGcAdTdT 1560 AD-39806.1GcAAuGAGGGAccAGuAcAdTdT 1134 UGuACUGGUCCCUcAUUGCdTdT 1561 AD-39812.1cAAuGAGGGAccAGuAcAudTdT 1135 AUGuACUGGUCCCUcAUUGdTdT 1562 AD-39818.1AAuGAGGGAccAGuAcAuGdTdT 1136 cAUGuACUGGUCCCUcAUUdTdT 1563 AD-39824.1AuGAGGGAccAGuAcAuGAdTdT 1137 UcAUGuACUGGUCCCUcAUdTdT 1564 AD-39783.1uGAGGGAccAGuAcAuGAGdTdT 1138 CUcAUGuACUGGUCCCUcAdTdT 1565 AD-39789.1GAGGGAccAGuAcAuGAGGdTdT 1139 CCUcAUGuACUGGUCCCUCdTdT 1566 AD-39795.1AGGGAccAGuAcAuGAGGAdTdT 1140 UCCUcAUGuACUGGUCCCUdTdT 1567 AD-39801.1GGGAccAGuAcAuGAGGAcdTdT 1141 GUCCUcAUGuACUGGUCCCdTdT 1568 AD-39807.1GGAccAGuAcAuGAGGAcudTdT 1142 AGUCCUcAUGuACUGGUCCdTdT 1569 AD-39813.1GAccAGuAcAuGAGGAcuGdTdT 1143 cAGUCCUcAUGuACUGGUCdTdT 1570 AD-39819.1AccAGuAcAuGAGGAcuGGdTdT 1144 CcAGUCCUcAUGuACUGGUdTdT 1571 AD-39825.1ccAGuAcAuGAGGAcuGGGdTdT 1145 CCcAGUCCUcAUGuACUGGdTdT 1572 AD-39831.1cAGuAcAuGAGGAcuGGGGdTdT 1146 CCCcAGUCCUcAUGuACUGdTdT 1573 AD-39837.1AGuAcAuGAGGAcuGGGGAdTdT 1147 UCCCcAGUCCUcAUGuACUdTdT 1574 AD-39843.1GuAcAuGAGGAcuGGGGAGdTdT 1148 CUCCCcAGUCCUcAUGuACdTdT 1575 AD-39849.1uAcAuGAGGAcuGGGGAGGdTdT 1149 CCUCCCcAGUCCUcAUGuAdTdT 1576 AD-39855.1AcAuGAGGAcuGGGGAGGGdTdT 1150 CCCUCCCcAGUCCUcAUGUdTdT 1577 AD-39861.1cAuGAGGAcuGGGGAGGGcdTdT 1151 GCCCUCCCcAGUCCUcAUGdTdT 1578 AD-39867.1AuGAGGAcuGGGGAGGGcudTdT 1152 AGCCCUCCCcAGUCCUcAUdTdT 1579 AD-39826.1uGAGGAcuGGGGAGGGcuudTdT 1153 AAGCCCUCCCcAGUCCUcAdTdT 1580 AD-39832.1GAGGAcuGGGGAGGGcuuudTdT 1154 AAAGCCCUCCCcAGUCCUCdTdT 1581 AD-39838.1AGGAcuGGGGAGGGcuuucdTdT 1155 GAAAGCCCUCCCcAGUCCUdTdT 1582 AD-39844.1GGAcuGGGGAGGGcuuucudTdT 1156 AGAAAGCCCUCCCcAGUCCdTdT 1583 AD-39850.1GAcuGGGGAGGGcuuucuudTdT 1157 AAGAAAGCCCUCCCcAGUCdTdT 1584 AD-39856.1AcuGGGGAGGGcuuucuuudTdT 1158 AAAGAAAGCCCUCCCcAGUdTdT 1585 AD-39862.1cuGGGGAGGGcuuucuuuGdTdT 1159 cAAAGAAAGCCCUCCCcAGdTdT 1586 AD-39868.1uGGGGAGGGcuuucuuuGudTdT 1160 AcAAAGAAAGCCCUCCCcAdTdT 1587 AD-39827.1uuGccAuAAAuAAuAcuAAdTdT 1161 UuAGuAUuAUUuAUGGcAAdTdT 1588 AD-39833.1uGccAuAAAuAAuAcuAAAdTdT 1162 UUuAGuAUuAUUuAUGGcAdTdT 1589 AD-39839.1GccAuAAAuAAuAcuAAAudTdT 1163 AUUuAGuAUuAUUuAUGGCdTdT 1590 AD-39845.1ccAuAAAuAAuAcuAAAucdTdT 1164 GAUUuAGuAUuAUUuAUGGdTdT 1591 AD-39851.1cAuAAAuAAuAcuAAAucAdTdT 1165 UGAUUuAGuAUuAUUuAUGdTdT 1592 AD-39857.1AuAAAuAAuAcuAAAucAudTdT 1166 AUGAUUuAGuAUuAUUuAUdTdT 1593 AD-39863.1uAAAuAAuAcuAAAucAuudTdT 1167 AAUGAUUuAGuAUuAUUuAdTdT 1594 AD-39869.1AAAuAAuAcuAAAucAuuudTdT 1168 AAAUGAUUuAGuAUuAUUUdTdT 1595 AD-39828.1AAuAAuAcuAAAucAuuuGdTdT 1169 cAAAUGAUUuAGuAUuAUUdTdT 1596 AD-39834.1AuAAuAcuAAAucAuuuGAdTdT 1170 UcAAAUGAUUuAGuAUuAUdTdT 1597 AD-39840.1uAAuAcuAAAucAuuuGAAdTdT 1171 UUcAAAUGAUUuAGuAUuAdTdT 1598 AD-39846.1AAuAcuAAAucAuuuGAAGdTdT 1172 CUUcAAAUGAUUuAGuAUUdTdT 1599 AD-39852.1AuAcuAAAucAuuuGAAGAdTdT 1173 UCUUcAAAUGAUUuAGuAUdTdT 1600 AD-39858.1uAcuAAAucAuuuGAAGAudTdT 1174 AUCUUcAAAUGAUUuAGuAdTdT 1601 AD-39864.1AcuAAAucAuuuGAAGAuAdTdT 1175 uAUCUUcAAAUGAUUuAGUdTdT 1602 AD-39870.1cuAAAucAuuuGAAGAuAudTdT 1176 AuAUCUUcAAAUGAUUuAGdTdT 1603 AD-39829.1uAAAucAuuuGAAGAuAuudTdT 1177 AAuAUCUUcAAAUGAUUuAdTdT 1604 AD-39835.1AAAucAuuuGAAGAuAuucdTdT 1178 GAAuAUCUUcAAAUGAUUUdTdT 1605 AD-39841.1AAucAuuuGAAGAuAuucAdTdT 1179 UGAAuAUCUUcAAAUGAUUdTdT 1606 AD-39853.1ucAuuuGAAGAuAuucAccdTdT 1180 GGUGAAuAUCUUcAAAUGAdTdT 1607 AD-39859.1cAuuuGAAGAuAuucAccAdTdT 1181 UGGUGAAuAUCUUcAAAUGdTdT 1608 AD-39865.1AuuuGAAGAuAuucAccAudTdT 1182 AUGGUGAAuAUCUUcAAAUdTdT 1609 AD-39871.1uuuGAAGAuAuucAccAuudTdT 1183 AAUGGUGAAuAUCUUcAAAdTdT 1610 AD-39830.1uuGAAGAuAuucAccAuuAdTdT 1184 uAAUGGUGAAuAUCUUcAAdTdT 1611 AD-39836.1GAGAAcAAAuuAAAAGAGudTdT 1185 ACUCUUUuAAUUUGUUCUCdTdT 1612 AD-39842.1AGAAcAAAuuAAAAGAGuudTdT 1186 AACUCUUUuAAUUUGUUCUdTdT 1613 AD-39848.1GAAcAAAuuAAAAGAGuuAdTdT 1187 uAACUCUUUuAAUUUGUUCdTdT 1614 AD-39854.1AAcAAAuuAAAAGAGuuAAdTdT 1188 UuAACUCUUUuAAUUUGUUdTdT 1615 AD-39860.1AcAAAuuAAAAGAGuuAAGdTdT 1189 CUuAACUCUUUuAAUUUGUdTdT 1616 AD-39866.1cAAAuuAAAAGAGuuAAGGdTdT 1190 CCUuAACUCUUUuAAUUUGdTdT 1617 AD-39992.1AAAuuAAAAGAGuuAAGGAdTdT 1191 UCCUuAACUCUUUuAAUUUdTdT 1618 AD-39998.1AAuuAAAAGAGuuAAGGAcdTdT 1192 GUCCUuAACUCUUUuAAUUdTdT 1619 AD-40004.1AuuAAAAGAGuuAAGGAcudTdT 1193 AGUCCUuAACUCUUUuAAUdTdT 1620 AD-40010.1uuAAAAGAGuuAAGGAcucdTdT 1194 GAGUCCUuAACUCUUUuAAdTdT 1621 AD-40016.1uAAAAGAGuuAAGGAcucudTdT 1195 AGAGUCCUuAACUCUUUuAdTdT 1622 AD-40022.1AAAAGAGuuAAGGAcucuGdTdT 1196 cAGAGUCCUuAACUCUUUUdTdT 1623 AD-40028.1AAAGAGuuAAGGAcucuGAdTdT 1197 UcAGAGUCCUuAACUCUUUdTdT 1624 AD-40034.1AAGAGuuAAGGAcucuGAAdTdT 1198 UUcAGAGUCCUuAACUCUUdTdT 1625 AD-39999.1GAGuuAAGGAcucuGAAGAdTdT 1199 UCUUcAGAGUCCUuAACUCdTdT 1626 AD-40005.1AGuuAAGGAcucuGAAGAudTdT 1200 AUCUUcAGAGUCCUuAACUdTdT 1627 AD-40011.1GuuAAGGAcucuGAAGAuGdTdT 1201 cAUCUUcAGAGUCCUuAACdTdT 1628 AD-40017.1uuAAGGAcucuGAAGAuGudTdT 1202 AcAUCUUcAGAGUCCUuAAdTdT 1629 AD-40029.1AAGGAcucuGAAGAuGuAcdTdT 1203 GuAcAUCUUcAGAGUCCUUdTdT 1630 AD-40035.1AGGAcucuGAAGAuGuAccdTdT 1204 GGuAcAUCUUcAGAGUCCUdTdT 1631 AD-39994.1GGAcucuGAAGAuGuAccudTdT 1205 AGGuAcAUCUUcAGAGUCCdTdT 1632 AD-40000.1GAcucuGAAGAuGuAccuAdTdT 1206 uAGGuAcAUCUUcAGAGUCdTdT 1633 AD-40006.1AcucuGAAGAuGuAccuAudTdT 1207 AuAGGuAcAUCUUcAGAGUdTdT 1634 AD-40012.1cucuGAAGAuGuAccuAuGdTdT 1208 cAuAGGuAcAUCUUcAGAGdTdT 1635 AD-40018.1ucuGAAGAuGuAccuAuGGdTdT 1209 CcAuAGGuAcAUCUUcAGAdTdT 1636 AD-40024.1cuGAAGAuGuAccuAuGGudTdT 1210 ACcAuAGGuAcAUCUUcAGdTdT 1637 AD-40030.1uGAAGAuGuAccuAuGGucdTdT 1211 GACcAuAGGuAcAUCUUcAdTdT 1638 AD-40036.1GuAGGAAAuAAAuGuGAuudTdT 1212 AAUcAcAUUuAUUUCCuACdTdT 1639 AD-39995.1uAGGAAAuAAAuGuGAuuudTdT 1213 AAAUcAcAUUuAUUUCCuAdTdT 1640 AD-40001.1AGGAAAuAAAuGuGAuuuGdTdT 1214 cAAAUcAcAUUuAUUUCCUdTdT 1641 AD-40007.1GGAAAuAAAuGuGAuuuGcdTdT 1215 GcAAAUcAcAUUuAUUUCCdTdT 1642 AD-40013.1GAAAuAAAuGuGAuuuGccdTdT 1216 GGcAAAUcAcAUUuAUUUCdTdT 1643 AD-40019.1AAAuAAAuGuGAuuuGccudTdT 1217 AGGcAAAUcAcAUUuAUUUdTdT 1644 AD-40025.1AAuAAAuGuGAuuuGccuudTdT 1218 AAGGcAAAUcAcAUUuAUUdTdT 1645 AD-40031.1AuAAAuGuGAuuuGccuucdTdT 1219 GAAGGcAAAUcAcAUUuAUdTdT 1646 AD-40037.1uAAAuGuGAuuuGccuucudTdT 1220 AGAAGGcAAAUcAcAUUuAdTdT 1647 AD-39996.1AAAuGuGAuuuGccuucuAdTdT 1221 uAGAAGGcAAAUcAcAUUUdTdT 1648 AD-40002.1AAuGuGAuuuGccuucuAGdTdT 1222 CuAGAAGGcAAAUcAcAUUdTdT 1649 AD-40008.1AuGuGAuuuGccuucuAGAdTdT 1223 UCuAGAAGGcAAAUcAcAUdTdT 1650 AD-40014.1uGuGAuuuGccuucuAGAAdTdT 1224 UUCuAGAAGGcAAAUcAcAdTdT 1651 AD-40020.1GuGAuuuGccuucuAGAAcdTdT 1225 GUUCuAGAAGGcAAAUcACdTdT 1652 AD-40026.1uGAuuuGccuucuAGAAcAdTdT 1226 UGUUCuAGAAGGcAAAUcAdTdT 1653 AD-40032.1GAuuuGccuucuAGAAcAGdTdT 1227 CUGUUCuAGAAGGcAAAUCdTdT 1654 AD-40038.1AuuuGccuucuAGAAcAGudTdT 1228 ACUGUUCuAGAAGGcAAAUdTdT 1655 AD-39997.1uuuGccuucuAGAAcAGuAdTdT 1229 uACUGUUCuAGAAGGcAAAdTdT 1656 AD-40009.1uGccuucuAGAAcAGuAGAdTdT 1230 UCuACUGUUCuAGAAGGcAdTdT 1657 AD-40015.1GccuucuAGAAcAGuAGAcdTdT 1231 GUCuACUGUUCuAGAAGGCdTdT 1658 AD-40021.1ccuucuAGAAcAGuAGAcAdTdT 1232 UGUCuACUGUUCuAGAAGGdTdT 1659 AD-40027.1cuucuAGAAcAGuAGAcAcdTdT 1233 GUGUCuACUGUUCuAGAAGdTdT 1660 AD-40033.1uucuAGAAcAGuAGAcAcAdTdT 1234 UGUGUCuACUGUUCuAGAAdTdT 1661 AD-40039.1ucuAGAAcAGuAGAcAcAAdTdT 1235 UUGUGUCuACUGUUCuAGAdTdT 1662 AD-40045.1cuAGAAcAGuAGAcAcAAAdTdT 1236 UUUGUGUCuACUGUUCuAGdTdT 1663 AD-40051.1uAGAAcAGuAGAcAcAAAAdTdT 1237 UUUUGUGUCuACUGUUCuAdTdT 1664 AD-40057.1AGAAcAGuAGAcAcAAAAcdTdT 1238 GUUUUGUGUCuACUGUUCUdTdT 1665 AD-40063.1GAAcAGuAGAcAcAAAAcAdTdT 1239 UGUUUUGUGUCuACUGUUCdTdT 1666 AD-40069.1AAcAGuAGAcAcAAAAcAGdTdT 1240 CUGUUUUGUGUCuACUGUUdTdT 1667 AD-40075.1AcAGuAGAcAcAAAAcAGGdTdT 1241 CCUGUUUUGUGUCuACUGUdTdT 1668 AD-40081.1cAGuAGAcAcAAAAcAGGcdTdT 1242 GCCUGUUUUGUGUCuACUGdTdT 1669 AD-40040.1AGuAGAcAcAAAAcAGGcudTdT 1243 AGCCUGUUUUGUGUCuACUdTdT 1670 AD-40046.1GuAGAcAcAAAAcAGGcucdTdT 1244 GAGCCUGUUUUGUGUCuACdTdT 1671 AD-40052.1uAGAcAcAAAAcAGGcucAdTdT 1245 UGAGCCUGUUUUGUGUCuAdTdT 1672 AD-40058.1AGAcAcAAAAcAGGcucAGdTdT 1246 CUGAGCCUGUUUUGUGUCUdTdT 1673 AD-40064.1GAcAcAAAAcAGGcucAGGdTdT 1247 CCUGAGCCUGUUUUGUGUCdTdT 1674 AD-40070.1AcAcAAAAcAGGcucAGGAdTdT 1248 UCCUGAGCCUGUUUUGUGUdTdT 1675 AD-40076.1cAcAAAAcAGGcucAGGAcdTdT 1249 GUCCUGAGCCUGUUUUGUGdTdT 1676 AD-40082.1AcAAAAcAGGcucAGGAcudTdT 1250 AGUCCUGAGCCUGUUUUGUdTdT 1677 AD-40041.1cAAAAcAGGcucAGGAcuudTdT 1251 AAGUCCUGAGCCUGUUUUGdTdT 1678 AD-40047.1AAAAcAGGcucAGGAcuuAdTdT 1252 uAAGUCCUGAGCCUGUUUUdTdT 1679 AD-40053.1AAAcAGGcucAGGAcuuAGdTdT 1253 CuAAGUCCUGAGCCUGUUUdTdT 1680 AD-40059.1AAcAGGcucAGGAcuuAGcdTdT 1254 GCuAAGUCCUGAGCCUGUUdTdT 1681 AD-40065.1AcAGGcucAGGAcuuAGcAdTdT 1255 UGCuAAGUCCUGAGCCUGUdTdT 1682 AD-40071.1cAGGcucAGGAcuuAGcAAdTdT 1256 UUGCuAAGUCCUGAGCCUGdTdT 1683 AD-40077.1AGGcucAGGAcuuAGcAAGdTdT 1257 CUUGCuAAGUCCUGAGCCUdTdT 1684 AD-40083.1GGcucAGGAcuuAGcAAGAdTdT 1258 UCUUGCuAAGUCCUGAGCCdTdT 1685 AD-40042.1GcucAGGAcuuAGcAAGAAdTdT 1259 UUCUUGCuAAGUCCUGAGCdTdT 1686 AD-40048.1cucAGGAcuuAGcAAGAAGdTdT 1260 CUUCUUGCuAAGUCCUGAGdTdT 1687 AD-40054.1ucAGGAcuuAGcAAGAAGudTdT 1261 ACUUCUUGCuAAGUCCUGAdTdT 1688 AD-40060.1cAGGAcuuAGcAAGAAGuudTdT 1262 AACUUCUUGCuAAGUCCUGdTdT 1689 AD-40066.1AGGAcuuAGcAAGAAGuuAdTdT 1263 uAACUUCUUGCuAAGUCCUdTdT 1690 AD-40072.1GGAcuuAGcAAGAAGuuAudTdT 1264 AuAACUUCUUGCuAAGUCCdTdT 1691 AD-40078.1GAcuuAGcAAGAAGuuAuGdTdT 1265 cAuAACUUCUUGCuAAGUCdTdT 1692 AD-40084.1AcuuAGcAAGAAGuuAuGGdTdT 1266 CcAuAACUUCUUGCuAAGUdTdT 1693 AD-40043.1cuuAGcAAGAAGuuAuGGAdTdT 1267 UCcAuAACUUCUUGCuAAGdTdT 1694 AD-40049.1uuAGcAAGAAGuuAuGGAAdTdT 1268 UUCcAuAACUUCUUGCuAAdTdT 1695 AD-40055.1uAGcAAGAAGuuAuGGAAudTdT 1269 AUUCcAuAACUUCUUGCuAdTdT 1696 AD-40061.1AGcAAGAAGuuAuGGAAuudTdT 1270 AAUUCcAuAACUUCUUGCUdTdT 1697 AD-40067.1GcAAGAAGuuAuGGAAuucdTdT 1271 GAAUUCcAuAACUUCUUGCdTdT 1698 AD-40073.1cAAGAAGuuAuGGAAuuccdTdT 1272 GGAAUUCcAuAACUUCUUGdTdT 1699 AD-40079.1AAGAAGuuAuGGAAuuccudTdT 1273 AGGAAUUCcAuAACUUCUUdTdT 1700 AD-40085.1AGAAGuuAuGGAAuuccuudTdT 1274 AAGGAAUUCcAuAACUUCUdTdT 1701 AD-40044.1GAAGuuAuGGAAuuccuuudTdT 1275 AAAGGAAUUCcAuAACUUCdTdT 1702 AD-40050.1AAGuuAuGGAAuuccuuuudTdT 1276 AAAAGGAAUUCcAuAACUUdTdT 1703 AD-40056.1AGuuAuGGAAuuccuuuuAdTdT 1277 uAAAAGGAAUUCcAuAACUdTdT 1704 AD-40062.1GuuAuGGAAuuccuuuuAudTdT 1278 AuAAAAGGAAUUCcAuAACdTdT 1705 AD-40068.1uuAuGGAAuuccuuuuAuudTdT 1279 AAuAAAAGGAAUUCcAuAAdTdT 1706 AD-40074.1uAuGGAAuuccuuuuAuuGdTdT 1280 cAAuAAAAGGAAUUCcAuAdTdT 1707 AD-40080.1AuGGAAuuccuuuuAuuGAdTdT 1281 UcAAuAAAAGGAAUUCcAUdTdT 1708 AD-39720.1ActtGtGGtAGttGGAGcttt 1792 AGCTCcAACtACcAcAAGTtt 1830 AD-39706.1GcAAGAGtGccttGAcGAttt 1793 ATCGTcAAGGcACTCTTGCtt 1831 AD-39712.1cAAGAGtGccttGAcGAtAtt 1794 tATCGTcAAGGcACTCTTGtt 1832 AD-39760.1ccttGAcGAtAcAGctAAttt 1795 ATtAGCTGtATCGTcAAGGtt 1833 AD-39732.1cAGctAAttcAGAAtcAtttt 1796 AATGATTCTGAATtAGCTGtt 1834 AD-35541.4cGAAtAtGAtccAAcAAtAtt 1797 tATTGTTGGATcAtATTCGtt 1835 AD-39735.1GGAAGcAAGtAGtAAttGAuu 1798 TcAATtACtACTTGCTTCCuu 1836 or hs_KRAS321_A22S26 AD-39741.1 GAAGcAAGtAGtAAttGAtuu 1799 ATcAATtACtACTTGCTTCuu1837 or hs_KRAS 322_A22S26 AD-39778.1 AGtAGtAAttGAtGGAGAAtt 1800TTCTCcATcAATtACtACTtt 1838 AD-39790.1 tAGtAAttGAtGGAGAAActt 1801GTTTCTCcATcAATtACtAtt 1839 AD-39822.1 GtctcttGGAtAttctcGAtt 1802TCGAGAAtATCcAAGAGACtt 1840 AD-35609.4 GGGctttctttGtGtAttttt 1803AAAtAcAcAAAGAAAGCCCtt 1841 AD-35581.4 GtGtAtttGccAtAAAtAAtt 1804TtATTtATGGcAAAtAcACtt 1842 AD-39845.1 ccAtAAAtAAtActAAAtctt 1805GATTtAGtATtATTtATGGtt 1843 AD-39858.1 tActAAAtcAtttGAAGAttt 1806ATCTTcAAATGATTtAGtAtt 1844 AD-39870.1 ctAAAtcAtttGAAGAtAtuu 1807AtATCTTcAAATGATTtAGuu 1845 AD-35576.4 GAAGAtAttcAccAttAtAtt 1808tAtAATGGTGAAtATCTTCtt 1846 AD-35588.4 AGAtAttcAccAttAtAGAtt 1809TCtAtAATGGTGAAtATCTtt 1847 AD-35600.1 AtAttcAccAttAtAGAGAtt 1810TCTCtAtAATGGTGAAtATtt 1848 AD-35606.1 tAttcAccAttAtAGAGAAtt 1811TTCTCtAtAATGGTGAAtAtt 1849 AD-38151.1 cAttAtAGAGAAcAAAttAtt 1812tAATTTGTTCTCtAtAATGtt 1850 AD-38163.1 ttAtAGAGAAcAAAttAAAtt 1813TTtAATTTGTTCTCtAtAAtt 1851 AD-39999.1 GAGttAAGGActctGAAGAtt 1814TCTTcAGAGTCCTtAACTCtt 1852 AD-38159.1 ctAtGGtcctAGtAGGAAAuu 1815TTTCCtACtAGGACcAtAGuu 1853 or hs_KRAS 528_A22S26 AD-38130.1tGGtcctAGtAGGAAAtAAuu 1816 TtATTTCCtACtAGGACcAuu 1854 or hs_KRAS531_A22S26 AD-38136.1 GGtcctAGtAGGAAAtAAAtt 1817 TTtATTTCCtACtAGGACCtt1855 AD-40036.1 GtAGGAAAtAAAtGtGAtttt 1818 AATcAcATTtATTTCCtACtt 1856AD-40008.1 AtGtGAtttGccttctAGAtt 1819 TCtAGAAGGcAAATcAcATtt 1857AD-40021.1 ccttctAGAAcAGtAGAcAtt 1820 TGTCtACTGTTCtAGAAGGtt 1858AD-40077.1 AGGctcAGGActtAGcAAGtt 1821 CTTGCtAAGTCCTGAGCCTtt 1859AD-40072.1 GGActtAGcAAGAAGttAttt 1822 AtAACTTCTTGCtAAGTCCtt 1860AD-40061.1 AGcAAGAAGttAtGGAAtttt 1823 AATTCcAtAACTTCTTGCTtt 1861AD-40068.1 ttAtGGAAttccttttAtttt 1824 AAtAAAAGGAATTCcAtAAtt 1862AD-38131.1 GGAAttccttttAttGAAAtt 1825 TTTcAAtAAAAGGAATTCCtt 1863AD-38167.1 ccttttAttGAAAcAtcAGtt 1826 CTGATGTTTcAAtAAAAGGtt 1864 hs_KRAScctGAtGAAtGtAAAGttAuu 1827 tAACTTtAcATTcATcAGGuu 1865 1273_A22S26hs_KRAS GGAGAAtttAAtAAAGAtAuu 1828 TATCTTtATtAAATTCTCCuu 18662892_A37S26 hs_KRAS GAAtAGtcAtAActAGAttuu 1829 AATCtAGTtATGACtATTCuu1867 4731_A22S26

Modifications of the sequences of RNAi agents are easily conceived byone of skill in the art. Examples and non-limiting modifications ofthese sequences are conceived and are also listed in Table 3. Note forexample, that many sequences end with a terminal dTdT. This is a variantof the TT terminal overhang known to protect siRNAs from nucleasedegradation (e.g., in blood serum or intestinal fluid). The dTdT or TTterminal overhangs are optional; they can be replaced by various typesof 3′ end caps, provided that the 3′ end caps are capable of bothmediating nuclease resistance and allowing siRNA activity.

Some modifications are placed at sites predicted to be sensitive toendonucleases.

Some modifications are designed to eliminate an immune response to thesiRNA while preserving activity. In general, the sense strand is heavilymodified, and the antisense strand lightly modified. Some modificationsserve more than one purpose.

The sequences in Table s 1 to 3 are represented by these abbreviations:

TABLE 1A ABBREVIATIONS Abbreviation Nucleotide(s) Aadenosine-5′-phosphate C cytidine-5′-phosphate G guanosine-5′-phosphatedT 2′-deoxy-thymidine-5′-phosphate U uridine-5′-phosphate c2′-O-methylcytidine-5′-phosphate u 2′-O-methyluridine-5′-phosphate sdT2′-deoxy Thymidine 5′-phosphorothioate

siRNA Sequence Selection

Sense and antisense human SCNNB1-derived siRNA oligos (RNAi agents toKRAS) are synthesized, as described herein. The sense and theirrespective antisense oligos are annealed into duplexes.

Example 2 Overlapping Sets of KRAS RNAi Agents

The present disclosure also relates to groups of RNAi agents to KRASwith overlapping sequences. Thus, the present disclosure encompassesgroups of RNAi agents wherein each RNAi agent in the group overlaps witheach other RNAi agent in the same group by at least 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19 or more nucleotides. Particularly, inone embodiment, the overlap is at least 12 nt.

Some of the RNAi agents listed herein overlap each other in sequence.Table 4 presents a compilation of some of these groups of overlappingRNAi agents, wherein each member of a group overlaps with each othermember of the same group by at least 12 nt. A 12-nt portion of theoverlap of the sense and anti-sense strand are presented.

Thus, for example, as shown in Table 4, the sequences of duplexesAD-39695.1, AD-39689.1,AD-39707.1, AD-39683.1, and AD-39701.1 alloverlap, wherein the overlap in sense strand comprises the sequenceCUGAAUAUAAAC (SEQ ID NO: 1874) and the overlap in the anti-sense strandcomprises the sequence GUUUAUAUUCAG (SEQ ID NO: 1875).

However, in the present disclosure encompasses any set or subset orgroup or subgroup of KRAS RNAi agents which share the common technicalfeature of a sequence overlap (e.g., by at least 12 nt). Thus thepresent disclosure also encompasses the example groups of AD-39695.1,AD-39689.1, AD-39707.1, AD-39683.1, and AD-39701.1, but also thesesubgroups: AD-39695.1 and AD-39689.1; AD-39695.1 and AD-39707.1;AD-39695.1, AD-39689.1, and AD-39701.1; AD-39689.1, AD-39707.1, andAD-39701.1; AD-39707.1 and AD-39683.1; AD-39707.1, AD-39683.1, andAD-39701.1; etc, and any other group of overlapping KRAS RNAi agents.

TABLE 4 Overlapping sets of KRAS RNAi agents SEQ SEQ ID Anti-sense IDSense overlap NO: overlap NO: Overlapping RNAi agents to KRASUGACUGAAUAUA 1868 UAUAUUCAGUCA 1869 AD-39689.1, AD-39683.1 GACUGAAUAUAA1870 UUAUAUUCAGUC 1871 AD-39695.1, AD-39689.1, AD-39683.1 ACUGAAUAUAAA1872 UUUAUAUUCAGU 1873 AD-39695.1, AD-39689.1, AD- 39683.1, AD-39701.1CUGAAUAUAAAC 1874 GUUUAUAUUCAG 1875 AD-39695.1, AD-39689.1, AD- 39707.1,AD-39683.1, AD-39701.1 UGAAUAUAAACU 1876 AGUUUAUAUUCA 1877 AD-39695.1,AD-39689.1, AD- 39713.1, AD-39707.1, AD-39683.1, AD- 39701.1GAAUAUAAACUU 1878 AAGUUUAUAUUC 1879 AD-39695.1, AD-39689.1, AD- 39713.1,AD-39707.1, AD-39683.1, AD- 39701.1, AD-39719.1 AAUAUAAACUUG 1880CAAGUUUAUAUU 1881 AD-39695.1, AD-39689.1, AD- 39713.1, AD-39707.1,AD-39683.1, AD- 39701.1, AD-39725.1, AD-39719.1 AUAUAAACUUGU 1882ACAAGUUUAUAU 1883 AD-39695.1, AD-39689.1, AD- 39713.1, AD-39707.1,AD-39701.1, AD- 39725.1, AD-39719.1, AD-39684.1 UAUAAACUUGUG 1884CACAAGUUUAUA 1885 AD-39690.1, AD-39695.1, AD- 39713.1, AD-39707.1,AD-39701.1, AD- 39725.1, AD-39719.1, AD-39684.1 AUAAACUUGUGG 1886CCACAAGUUUAU 1887 AD-39690.1, AD-39713.1, AD- 39707.1, AD-39701.1,AD-39725.1, AD- 39719.1, AD-39684.1, AD-39696.1 UAAACUUGUGGU 1888ACCACAAGUUUA 1889 AD-39690.1, AD-39713.1, AD- 39707.1, AD-39725.1,AD-39702.1, AD- 39719.1, AD-39684.1, AD-39696.1 AAACUUGUGGUA 1890UACCACAAGUUU 1891 AD-39690.1, AD-39713.1, AD- 39725.1, AD-39702.1,AD-39719.1, AD- 39684.1, AD-39696.1, AD-39708.1 AACUUGUGGUAG 1892CUACCACAAGUU 1893 AD-39690.1, AD-39725.1, AD- 39702.1, AD-39719.1,AD-39684.1, AD- 39714.1, AD-39696.1, AD-39708.1 ACUUGUGGUAGU 1894ACUACCACAAGU 1895 AD-39690.1, AD-39725.1, AD- 39702.1, AD-39684.1,AD-39714.1, AD- 39696.1, AD-39708.1, AD-39720.1 CUUGUGGUAGUU 1896AACUACCACAAG 1897 AD-39690.1, AD-39702.1, AD- 39684.1, AD-39714.1,AD-39696.1, AD- 39708.1, AD-39720.1, AD-39726.1 UUGUGGUAGUUG 1898CAACUACCACAA 1899 AD-39690.1, AD-39702.1, AD- 39714.1, AD-39696.1,AD-39708.1, AD- 39720.1, AD-39726.1, AD-39685.1 UGUGGUAGUUGG 1900CCAACUACCACA 1901 AD-39691.1, AD-39702.1, AD- 39714.1, AD-39696.1,AD-39708.1, AD- 39720.1, AD-39726.1, AD-39685.1 GUGGUAGUUGGA 1902UCCAACUACCAC 1903 AD-39691.1, AD-39697.1, AD- 39702.1, AD-39714.1,AD-39708.1, AD- 39720.1, AD-39726.1, AD-39685.1 UGGUAGUUGGAG 1904CUCCAACUACCA 1905 AD-39703.1, AD-39691.1, AD- 39697.1, AD-39714.1,AD-39708.1, AD- 39720.1, AD-39726.1, AD-39685.1 GGUAGUUGGAGC 1906GCUCCAACUACC 1907 AD-39703.1, AD-39691.1, AD- 39697.1, AD-39714.1,AD-39709.1, AD- 39720.1, AD-39726.1, AD-39685.1 GUAGUUGGAGCU 1908AGCUCCAACUAC 1909 AD-39703.1, AD-39691.1, AD- 39697.1, AD-39715.1,AD-39709.1, AD- 39720.1, AD-39726.1, AD-39685.1 UAGUUGGAGCUG 1910CAGCUCCAACUA 1911 AD-39703.1, AD-39691.1, AD- 39697.1, AD-39715.1,AD-39709.1, AD- 39721.1, AD-39726.1, AD-39685.1 AGUUGGAGCUGG 1912CCAGCUCCAACU 1913 AD-39703.1, AD-39691.1, AD- 39697.1, AD-39715.1,AD-39709.1, AD- 39721.1, AD-39727.1, AD-39685.1 GUUGGAGCUGGU 1914ACCAGCUCCAAC 1915 AD-39703.1, AD-39691.1, AD- 39686.1, AD-39697.1,AD-39715.1, AD- 39709.1, AD-39721.1, AD-39727.1 UUGGAGCUGGUG 1916CACCAGCUCCAA 1917 AD-39703.1, AD-39686.1, AD- 39697.1, AD-39692.1,AD-39715.1, AD- 39709.1, AD-39721.1, AD-39727.1 UGGAGCUGGUGG 1918CCACCAGCUCCA 1919 AD-39703.1, AD-39686.1, AD- 39692.1, AD-39715.1,AD-39709.1, AD- 39698.1, AD-39721.1, AD-39727.1 GGAGCUGGUGGC 1920GCCACCAGCUCC 1921 AD-39686.1, AD-39692.1, AD- 39715.1, AD-39709.1,AD-39698.1, AD- 39721.1, AD-39704.1, AD-39727.1 GAGCUGGUGGCG 1922CGCCACCAGCUC 1923 AD-39710.1, AD-39686.1, AD- 39692.1, AD-39715.1,AD-39698.1, AD- 39721.1, AD-39704.1, AD-39727.1 AGCUGGUGGCGU 1924ACGCCACCAGCU 1925 AD-39710.1, AD-39686.1, AD- 39692.1, AD-39716.1,AD-39698.1, AD- 39721.1, AD-39704.1, AD-39727.1 GCUGGUGGCGUA 1926UACGCCACCAGC 1927 AD-39710.1, AD-39686.1, AD- 39692.1, AD-39722.1,AD-39716.1, AD- 39698.1, AD-39704.1, AD-39727.1 CUGGUGGCGUAG 1928CUACGCCACCAG 1929 AD-39710.1, AD-39686.1, AD- 39692.1, AD-39722.1,AD-39716.1, AD- 39728.1, AD-39698.1, AD-39704.1 UGGUGGCGUAGG 1930CCUACGCCACCA 1931 AD-39710.1, AD-39687.1, AD- 39692.1, AD-39722.1,AD-39716.1, AD- 39728.1, AD-39698.1, AD-39704.1 GGUGGCGUAGGC 1932GCCUACGCCACC 1933 AD-39693.1, AD-39710.1, AD- 39687.1, AD-39722.1,AD-39716.1, AD- 39728.1, AD-39698.1, AD-39704.1 GUGGCGUAGGCA 1934UGCCUACGCCAC 1935 AD-39693.1, AD-39710.1, AD- 39699.1, AD-39687.1,AD-39722.1, AD- 39716.1, AD-39728.1, AD-39704.1 UGGCGUAGGCAA 1936UUGCCUACGCCA 1937 AD-39693.1, AD-39710.1, AD- 39699.1, AD-39687.1,AD-39722.1, AD- 39716.1, AD-39705.1, AD-39728.1 GGCGUAGGCAAG 1938CUUGCCUACGCC 1939 AD-39693.1, AD-39699.1, AD- 39687.1, AD-39711.1,AD-39722.1, AD- 39716.1, AD-39705.1, AD-39728.1 GCGUAGGCAAGA 1940UCUUGCCUACGC 1941 AD-39693.1, AD-39699.1, AD- 39687.1, AD-39717.1,AD-39711.1, AD- 39722.1, AD-39705.1, AD-39728.1 CGUAGGCAAGAG 1942CUCUUGCCUACG 1943 AD-39693.1, AD-39699.1, AD- 39687.1, AD-39717.1,AD-39711.1, AD- 39705.1, AD-39728.1, AD-39723.1 GUAGGCAAGAGU 1944ACUCUUGCCUAC 1945 AD-39693.1, AD-39699.1, AD- 39687.1, AD-39717.1,AD-39711.1, AD- 39729.1, AD-39705.1, AD-39723.1 UAGGCAAGAGUG 1946CACUCUUGCCUA 1947 AD-39693.1, AD-39699.1, AD- 39717.1, AD-39711.1,AD-39688.1, AD- 39729.1, AD-39705.1, AD-39723.1 AGGCAAGAGUGC 1948GCACUCUUGCCU 1949 AD-39699.1, AD-39717.1, AD- 39711.1, AD-39688.1,AD-39729.1, AD- 39705.1, AD-39694.1, AD-39723.1 GGCAAGAGUGCC 1950GGCACUCUUGCC 1951 AD-39717.1, AD-39711.1, AD- 39688.1, AD-39729.1,AD-39705.1, AD- 39694.1, AD-39700.1, AD-39723.1 GCAAGAGUGCCU 1952AGGCACUCUUGC 1953 AD-39717.1, AD-39711.1, AD- 39688.1, AD-39729.1,AD-39706.1, AD- 39694.1, AD-39700.1, AD-39723.1 CAAGAGUGCCUU 1954AAGGCACUCUUG 1955 AD-39712.1, AD-39717.1, AD- 39688.1, AD-39729.1,AD-39706.1, AD- 39694.1, AD-39700.1, AD-39723.1 AAGAGUGCCUUG 1956CAAGGCACUCUU 1957 AD-39718.1, AD-39712.1, AD- 39688.1, AD-39729.1,AD-39706.1, AD- 39694.1, AD-39700.1, AD-39723.1 AGAGUGCCUUGA 1958UCAAGGCACUCU 1959 AD-39718.1, AD-39712.1, AD- 39724.1, AD-39688.1,AD-39729.1, AD- 39706.1, AD-39694.1, AD-39700.1 GAGUGCCUUGAC 1960GUCAAGGCACUC 1961 AD-39718.1, AD-39712.1, AD- 39724.1, AD-39688.1,AD-39706.1, AD- 39694.1, AD-39700.1, AD-39730.1 AGUGCCUUGACG 1962CGUCAAGGCACU 1963 AD-39718.1, AD-39712.1, AD- 39724.1, AD-39706.1,AD-39694.1, AD- 39736.1, AD-39700.1, AD-39730.1 GUGCCUUGACGA 1964UCGUCAAGGCAC 1965 AD-39718.1, AD-39712.1, AD- 39724.1, AD-39742.1,AD-39706.1, AD- 39736.1, AD-39700.1, AD-39730.1 UGCCUUGACGAU 1966AUCGUCAAGGCA 1967 AD-39718.1, AD-39712.1, AD- 39724.1, AD-39742.1,AD-39706.1, AD- 39736.1, AD-39748.1, AD-39730.1 GCCUUGACGAUA 1968UAUCGUCAAGGC 1969 AD-39718.1, AD-39712.1, AD- 39724.1, AD-39742.1,AD-39754.1, AD- 39736.1, AD-39748.1, AD-39730.1 CCUUGACGAUAC 1970GUAUCGUCAAGG 1971 AD-39718.1, AD-39724.1, AD- 39742.1, AD-39754.1,AD-39736.1, AD- 39748.1, AD-39760.1, AD-39730.1 CUUGACGAUACA 1972UGUAUCGUCAAG 1973 AD-39724.1, AD-39742.1, AD- 39754.1, AD-39736.1,AD-39748.1, AD- 39760.1, AD-39730.1, AD-39766.1 UUGACGAUACAG 1974CUGUAUCGUCAA 1975 AD-39742.1, AD-39772.1, AD- 39754.1, AD-39736.1,AD-39748.1, AD- 39760.1, AD-39730.1, AD-39766.1 UGACGAUACAGC 1976GCUGUAUCGUCA 1977 AD-39742.1, AD-39772.1, AD- 39754.1, AD-39736.1,AD-39731.1, AD- 39748.1, AD-39760.1, AD-39766.1 GACGAUACAGCU 1978AGCUGUAUCGUC 1979 AD-39737.1, AD-39742.1, AD- 39772.1, AD-39754.1,AD-39731.1, AD- 39748.1, AD-39760.1, AD-39766.1 ACGAUACAGCUA 1980UAGCUGUAUCGU 1981 AD-39737.1, AD-39772.1, AD- 39754.1, AD-39743.1,AD-39731.1, AD- 39748.1, AD-39760.1, AD-39766.1 CGAUACAGCUAA 1982UUAGCUGUAUCG 1983 AD-39737.1, AD-39772.1, AD- 39754.1, AD-39743.1,AD-39731.1, AD- 39760.1, AD-39749.1, AD-39766.1 GAUACAGCUAAU 1984AUUAGCUGUAUC 1985 AD-39737.1, AD-39772.1, AD- 39743.1, AD-39731.1,AD-39760.1, AD- 39749.1, AD-39755.1, AD-39766.1 AUACAGCUAAUU 1986AAUUAGCUGUAU 1987 AD-39761.1, AD-39737.1, AD- 39772.1, AD-39743.1,AD-39731.1, AD- 39749.1, AD-39755.1, AD-39766.1 UACAGCUAAUUC 1988GAAUUAGCUGUA 1989 AD-39767.1, AD-39761.1, AD- 39737.1, AD-39772.1,AD-39743.1, AD- 39731.1, AD-39749.1, AD-39755.1 ACAGCUAAUUCA 1990UGAAUUAGCUGU 1991 AD-39767.1, AD-39761.1, AD- 39737.1, AD-39743.1,AD-39731.1, AD- 39773.1, AD-39749.1, AD-39755.1 CAGCUAAUUCAG 1992CUGAAUUAGCUG 1993 AD-39767.1, AD-39761.1, AD- 39737.1, AD-39732.1,AD-39743.1, AD- 39773.1, AD-39749.1, AD-39755.1 AGCUAAUUCAGA 1994UCUGAAUUAGCU 1995 AD-39767.1, AD-39761.1, AD- 39732.1, AD-39743.1,AD-39738.1, AD- 39773.1, AD-39749.1, AD-39755.1 GCUAAUUCAGAA 1996UUCUGAAUUAGC 1997 AD-39767.1, AD-39761.1, AD- 39744.1, AD-39732.1,AD-39738.1, AD- 39773.1, AD-39749.1, AD-39755.1 CUAAUUCAGAAU 1998AUUCUGAAUUAG 1999 AD-39767.1, AD-39761.1, AD- 39744.1, AD-39732.1,AD-39750.1, AD- 39738.1, AD-39773.1, AD-39755.1 UAAUUCAGAAUC 2000GAUUCUGAAUUA 2001 AD-39756.1, AD-39767.1, AD- 39761.1, AD-39744.1,AD-39732.1, AD- 39750.1, AD-39738.1, AD-39773.1 AAUUCAGAAUCA 2002UGAUUCUGAAUU 2003 AD-39756.1, AD-39767.1, AD- 39744.1, AD-39762.1,AD-39732.1, AD- 39750.1, AD-39738.1, AD-39773.1 AUUCAGAAUCAU 2004AUGAUUCUGAAU 2005 AD-39756.1, AD-39744.1, AD- 39762.1, AD-39732.1,AD-39768.1, AD- 39750.1, AD-39738.1, AD-39773.1 UUCAGAAUCAUU 2006AAUGAUUCUGAA 2007 AD-39756.1, AD-39774.1, AD- 39744.1, AD-39762.1,AD-39732.1, AD- 39768.1, AD-39750.1, AD-39738.1 UCAGAAUCAUUU 2008AAAUGAUUCUGA 2009 AD-39756.1, AD-39774.1, AD- 39744.1, AD-39762.1,AD-39733.1, AD- 39768.1, AD-39750.1, AD-39738.1 CAGAAUCAUUUU 2010AAAAUGAUUCUG 2011 AD-39756.1, AD-39739.1, AD- 39774.1, AD-39744.1,AD-39762.1, AD- 39733.1, AD-39768.1, AD-39750.1 AGAAUCAUUUUG 2012CAAAAUGAUUCU 2013 AD-39745.1, AD-39756.1, AD- 39739.1, AD-39774.1,AD-39762.1, AD- 39733.1, AD-39768.1, AD-39750.1 GAAUCAUUUUGU 2014ACAAAAUGAUUC 2015 AD-39745.1, AD-39756.1, AD- 39739.1, AD-39774.1,AD-39762.1, AD- 39733.1, AD-39768.1, AD-39751.1 AAUCAUUUUGUG 2016CACAAAAUGAUU 2017 AD-39745.1, AD-39739.1, AD- 39774.1, AD-39757.1,AD-39762.1, AD- 39733.1, AD-39768.1, AD-39751.1 AUCAUUUUGUGG 2018CCACAAAAUGAU 2019 AD-39745.1, AD-39739.1, AD- 39774.1, AD-39757.1,AD-39733.1, AD- 39768.1, AD-39751.1, AD-39763.1 UCAUUUUGUGGA 2020UCCACAAAAUGA 2021 AD-39745.1, AD-39739.1, AD- 39774.1, AD-39757.1,AD-39733.1, AD- 39751.1, AD-39769.1, AD-39763.1 CAUUUUGUGGAC 2022GUCCACAAAAUG 2023 AD-39745.1, AD-39739.1, AD- 39775.1, AD-39757.1,AD-39733.1, AD- 39751.1, AD-39769.1, AD-39763.1 AUUUUGUGGACG 2024CGUCCACAAAAU 2025 AD-39745.1, AD-39739.1, AD- 39775.1, AD-39757.1,AD-39751.1, AD- 39769.1, AD-39763.1, AD-39734.1 UUUUGUGGACGA 2026UCGUCCACAAAA 2027 AD-39745.1, AD-39775.1, AD- 39757.1, AD-39751.1,AD-39769.1, AD- 39740.1, AD-39763.1, AD-39734.1 UUUGUGGACGAA 2028UUCGUCCACAAA 2029 AD-39775.1, AD-39746.1, AD- 39757.1, AD-39751.1,AD-39769.1, AD- 39740.1, AD-39763.1, AD-39734.1 UUGUGGACGAAU 2030AUUCGUCCACAA 2031 AD-39752.1, AD-39775.1, AD- 39746.1, AD-39757.1,AD-39769.1, AD- 39740.1, AD-39763.1, AD-39734.1 UGUGGACGAAUA 2032UAUUCGUCCACA 2033 AD-39752.1, AD-39775.1, AD- 39746.1, AD-39758.1,AD-39769.1, AD- 39740.1, AD-39763.1, AD-39734.1 GUGGACGAAUAU 2034AUAUUCGUCCAC 2035 AD-39752.1, AD-39775.1, AD- 39764.1, AD-39746.1,AD-39758.1, AD- 39769.1, AD-39740.1, AD-39734.1 UGGACGAAUAUG 2036CAUAUUCGUCCA 2037 AD-39752.1, AD-39775.1, AD- 39764.1, AD-39746.1,AD-39770.1, AD- 39758.1, AD-39740.1, AD-39734.1 GGACGAAUAUGA 2038UCAUAUUCGUCC 2039 AD-39752.1, AD-35523.3, AD- 39764.1, AD-39746.1,AD-39770.1, AD- 39758.1, AD-39740.1, AD-39734.1 GACGAAUAUGAU 2040AUCAUAUUCGUC 2041 AD-39752.1, AD-35529.1, AD- 35523.3, AD-39764.1,AD-39746.1, AD- 39770.1, AD-39758.1, AD-39740.1 ACGAAUAUGAUC 2042GAUCAUAUUCGU 2043 AD-39752.1, AD-35529.1, AD- 35523.3, AD-39764.1,AD-39746.1, AD- 35535.4, AD-39770.1, AD-39758.1 CGAAUAUGAUCC 2044GGAUCAUAUUCG 2045 AD-39752.1, AD-35529.1, AD- 35523.3, AD-35541.4,AD-39764.1, AD- 35535.4, AD-39770.1, AD-39758.1 GAAUAUGAUCCA 2046UGGAUCAUAUUC 2047 AD-35529.1, AD-35523.3, AD- 35541.4, AD-39764.1,AD-35535.4, AD- 39770.1, AD-39758.1, AD-35547.4 AAUAUGAUCCAA 2048UUGGAUCAUAUU 2049 AD-35529.1, AD-35523.3, AD- 35541.4, AD-39764.1,AD-35535.4, AD- 39770.1, AD-35553.4, AD-35547.4 AUAUGAUCCAAC 2050GUUGGAUCAUAU 2051 AD-35529.1, AD-35523.3, AD- 35541.4, AD-35559.4,AD-35535.4, AD- 39770.1, AD-35553.4, AD-35547.4 UAUGAUCCAACA 2052UGUUGGAUCAUA 2053 AD-35529.1, AD-35523.3, AD- 35541.4, AD-35565.4,AD-35559.4, AD- 35535.4, AD-35553.4, AD-35547.4 AUGAUCCAACAA 2054UUGUUGGAUCAU 2055 AD-35529.1, AD-35541.4, AD- 35565.4, AD-35559.4,AD-35535.4, AD- 35553.4, AD-35547.4, AD-35524.4 UGAUCCAACAAU 2056AUUGUUGGAUCA 2057 AD-35530.4, AD-35541.4, AD- 35565.4, AD-35559.4,AD-35535.4, AD- 35553.4, AD-35547.4, AD-35524.4 GAUCCAACAAUA 2058UAUUGUUGGAUC 2059 AD-35530.4, AD-35541.4, AD- 35565.4, AD-35559.4,AD-35553.4, AD- 35536.4, AD-35547.4, AD-35524.4 AUCCAACAAUAG 2060CUAUUGUUGGAU 2061 AD-35530.4, AD-35565.4, AD- 35559.4, AD-35553.4,AD-35542.4, AD- 35536.4, AD-35547.4, AD-35524.4 UCCAACAAUAGA 2062UCUAUUGUUGGA 2063 AD-35530.4, AD-35565.4, AD- 35559.4, AD-35553.4,AD-35548.4, AD- 35542.4, AD-35536.4, AD-35524.4 CCAACAAUAGAG 2064CUCUAUUGUUGG 2065 AD-35554.4, AD-35530.4, AD- 35565.4, AD-35559.4,AD-35548.4, AD- 35542.4, AD-35536.4, AD-35524.4 CAACAAUAGAGG 2066CCUCUAUUGUUG 2067 AD-35554.4, AD-35530.4, AD- 35565.4, AD-35548.4,AD-35542.4, AD- 35536.4, AD-35560.2, AD-35524.4 AACAAUAGAGGA 2068UCCUCUAUUGUU 2069 AD-35554.4, AD-35530.4, AD- 35566.4, AD-35548.4,AD-35542.4, AD- 35536.4, AD-35560.2, AD-35524.4 ACAAUAGAGGAU 2070AUCCUCUAUUGU 2071 AD-35554.4, AD-35530.4, AD- 35525.2, AD-35566.4,AD-35548.4, AD- 35542.4, AD-35536.4, AD-35560.2 CAAUAGAGGAUU 2072AAUCCUCUAUUG 2073 AD-35554.4, AD-35525.2, AD- 35566.4, AD-35548.4,AD-35542.4, AD- 35536.4, AD-35531.4, AD-35560.2 AAUAGAGGAUUC 2074GAAUCCUCUAUU 2075 AD-35554.4, AD-35525.2, AD- 35537.4, AD-35566.4,AD-35548.4, AD- 35542.4, AD-35531.4, AD-35560.2 AUAGAGGAUUCC 2076GGAAUCCUCUAU 2077 AD-35554.4, AD-35525.2, AD- 35537.4, AD-35566.4,AD-35548.4, AD- 35531.4, AD-35560.2, AD-35543.2 UAGAGGAUUCCU 2078AGGAAUCCUCUA 2079 AD-35549.4, AD-35554.4, AD- 35525.2, AD-35537.4,AD-35566.4, AD- 35531.4, AD-35560.2, AD-35543.2 AGAGGAUUCCUA 2080UAGGAAUCCUCU 2081 AD-35549.4, AD-35555.4, AD- 35525.2, AD-35537.4,AD-35566.4, AD- 35531.4, AD-35560.2, AD-35543.2 GAGGAUUCCUAC 2082GUAGGAAUCCUC 2083 AD-35549.4, AD-35555.4, AD- 35525.2, AD-35537.4,AD-35566.4, AD- 35531.4, AD-35561.4, AD-35543.2 AGGAUUCCUACA 2084UGUAGGAAUCCU 2085 AD-35549.4, AD-35555.4, AD- 35525.2, AD-35537.4,AD-35531.4, AD- 35561.4, AD-35543.2, AD-35567.4 GGAUUCCUACAG 2086CUGUAGGAAUCC 2087 AD-35549.4, AD-35555.4, AD- 35526.4, AD-35537.4,AD-35531.4, AD- 35561.4, AD-35543.2, AD-35567.4 GAUUCCUACAGG 2088CCUGUAGGAAUC 2089 AD-35549.4, AD-35555.4, AD- 35532.4, AD-35526.4,AD-35537.4, AD- 35561.4, AD-35543.2, AD-35567.4 AUUCCUACAGGA 2090UCCUGUAGGAAU 2091 AD-35549.4, AD-35555.4, AD- 35532.4, AD-35526.4,AD-35538.4, AD- 35561.4, AD-35543.2, AD-35567.4 UUCCUACAGGAA 2092UUCCUGUAGGAA 2093 AD-35549.4, AD-35555.4, AD- 35532.4, AD-35526.4,AD-35538.4, AD- 35544.4, AD-35561.4, AD-35567.4 UCCUACAGGAAG 2094CUUCCUGUAGGA 2095 AD-35555.4, AD-35532.4, AD- 35526.4, AD-35550.4,AD-35538.4, AD- 35544.4, AD-35561.4, AD-35567.4 CCUACAGGAAGC 2096GCUUCCUGUAGG 2097 AD-35556.4, AD-35532.4, AD- 35526.4, AD-35550.4,AD-35538.4, AD- 35544.4, AD-35561.4, AD-35567.4 CUACAGGAAGCA 2098UGCUUCCUGUAG 2099 AD-35562.4, AD-35556.4, AD- 35532.4, AD-35526.4,AD-35550.4, AD- 35538.4, AD-35544.4, AD-35567.4 UACAGGAAGCAA 2100UUGCUUCCUGUA 2101 AD-35562.4, AD-35556.4, AD- 35532.4, AD-35526.4,AD-35550.4, AD- 35568.4, AD-35538.4, AD-35544.4 ACAGGAAGCAAG 2102CUUGCUUCCUGU 2103 AD-35562.4, AD-35556.4, AD- 35532.4, AD-35550.4,AD-35568.4, AD- 35538.4, AD-35544.4, AD-35527.4 CAGGAAGCAAGU 2104ACUUGCUUCCUG 2105 AD-35562.4, AD-35556.4, AD- 35550.4, AD-35568.4,AD-35538.4, AD- 35544.4, AD-35533.4, AD-35527.4 AGGAAGCAAGUA 2106UACUUGCUUCCU 2107 AD-35562.4, AD-35556.4, AD- 35550.4, AD-39776.1,AD-35568.4, AD- 35544.4, AD-35533.4, AD-35527.4 GGAAGCAAGUAG 2108CUACUUGCUUCC 2109 AD-35562.4, AD-39735.1, AD- 35556.4, AD-35550.4,AD-39776.1, AD- 35568.4, AD-35533.4, AD-35527.4 GAAGCAAGUAGU 2110ACUACUUGCUUC 2111 AD-35562.4, AD-39735.1, AD- 35556.4, AD-39776.1,AD-35568.4, AD- 35533.4, AD-35527.4, AD-39741.1 AAGCAAGUAGUA 2112UACUACUUGCUU 2113 AD-35562.4, AD-39735.1, AD- 39776.1, AD-35568.4,AD-39747.1, AD- 35533.4, AD-35527.4, AD-39741.1 AGCAAGUAGUAA 2114UUACUACUUGCU 2115 AD-39735.1, AD-39753.1, AD- 39776.1, AD-35568.4,AD-39747.1, AD- 35533.4, AD-35527.4, AD-39741.1 GCAAGUAGUAAU 2116AUUACUACUUGC 2117 AD-39735.1, AD-39759.1, AD- 39753.1, AD-39776.1,AD-39747.1, AD- 35533.4, AD-35527.4, AD-39741.1 CAAGUAGUAAUU 2118AAUUACUACUUG 2119 AD-39735.1, AD-39759.1, AD- 39753.1, AD-39776.1,AD-39747.1, AD- 35533.4, AD-39765.1, AD-39741.1 AAGUAGUAAUUG 2120CAAUUACUACUU 2121 AD-39735.1, AD-39771.1, AD- 39759.1, AD-39753.1,AD-39776.1, AD- 39747.1, AD-39765.1, AD-39741.1 AGUAGUAAUUGA 2122UCAAUUACUACU 2123 AD-39735.1, AD-39778.1, AD- 39771.1, AD-39759.1,AD-39753.1, AD- 39747.1, AD-39765.1, AD-39741.1 GUAGUAAUUGAU 2124AUCAAUUACUAC 2125 AD-39784.1, AD-39778.1, AD- 39771.1, AD-39759.1,AD-39753.1, AD- 39747.1, AD-39765.1, AD-39741.1 UAGUAAUUGAUG 2126CAUCAAUUACUA 2127 AD-39784.1, AD-39778.1, AD- 39771.1, AD-39759.1,AD-39753.1, AD- 39747.1, AD-39765.1, AD-39790.1 AGUAAUUGAUGG 2128CCAUCAAUUACU 2129 AD-39784.1, AD-39778.1, AD- 39771.1, AD-39759.1,AD-39753.1, AD- 39796.1, AD-39765.1, AD-39790.1 GUAAUUGAUGGA 2130UCCAUCAAUUAC 2131 AD-39784.1, AD-39778.1, AD- 39771.1, AD-39759.1,AD-39796.1, AD- 39765.1, AD-39802.1, AD-39790.1 UAAUUGAUGGAG 2132CUCCAUCAAUUA 2133 AD-39784.1, AD-39778.1, AD- 39808.1, AD-39771.1,AD-39796.1, AD- 39765.1, AD-39802.1, AD-39790.1 AAUUGAUGGAGA 2134UCUCCAUCAAUU 2135 AD-39784.1, AD-39814.1, AD- 39778.1, AD-39808.1,AD-39771.1, AD- 39796.1, AD-39802.1, AD-39790.1 AUUGAUGGAGAA 2136UUCUCCAUCAAU 2137 AD-39784.1, AD-39814.1, AD- 39778.1, AD-39808.1,AD-39820.1, AD- 39796.1, AD-39802.1, AD-39790.1 UUGAUGGAGAAA 2138UUUCUCCAUCAA 2139 AD-39784.1, AD-39814.1, AD- 39808.1, AD-39820.1,AD-39779.1, AD- 39796.1, AD-39802.1, AD-39790.1 UGAUGGAGAAAC 2140GUUUCUCCAUCA 2141 AD-39814.1, AD-39808.1, AD- 39785.1, AD-39820.1,AD-39779.1, AD- 39796.1, AD-39802.1, AD-39790.1 GAUGGAGAAACC 2142GGUUUCUCCAUC 2143 AD-39791.1, AD-39814.1, AD- 39808.1, AD-39785.1,AD-39820.1, AD- 39779.1, AD-39796.1, AD-39802.1 AUGGAGAAACCU 2144AGGUUUCUCCAU 2145 AD-39791.1, AD-39814.1, AD- 39808.1, AD-39785.1,AD-39820.1, AD- 39779.1, AD-39797.1, AD-39802.1 UGGAGAAACCUG 2146CAGGUUUCUCCA 2147 AD-39791.1, AD-39814.1, AD- 39808.1, AD-39803.1,AD-39785.1, AD- 39820.1, AD-39779.1, AD-39797.1 GGAGAAACCUGU 2148ACAGGUUUCUCC 2149 AD-39791.1, AD-39814.1, AD- 39803.1, AD-39785.1,AD-39820.1, AD- 39809.1, AD-39779.1, AD-39797.1 GAGAAACCUGUC 2150GACAGGUUUCUC 2151 AD-39815.1, AD-39791.1, AD- 39803.1, AD-39785.1,AD-39820.1, AD- 39809.1, AD-39779.1, AD-39797.1 AGAAACCUGUCU 2152AGACAGGUUUCU 2153 AD-39815.1, AD-39791.1, AD- 39803.1, AD-39821.1,AD-39785.1, AD- 39809.1, AD-39779.1, AD-39797.1 GAAACCUGUCUC 2154GAGACAGGUUUC 2155 AD-39815.1, AD-39791.1, AD- 39803.1, AD-39821.1,AD-39785.1, AD- 39809.1, AD-39780.1, AD-39797.1 AAACCUGUCUCU 2156AGAGACAGGUUU 2157 AD-39815.1, AD-39791.1, AD- 39803.1, AD-39821.1,AD-39809.1, AD- 39780.1, AD-39797.1, AD-39786.1 AACCUGUCUCUU 2158AAGAGACAGGUU 2159 AD-39815.1, AD-39803.1, AD- 39821.1, AD-39809.1,AD-39792.1, AD- 39780.1, AD-39797.1, AD-39786.1 ACCUGUCUCUUG 2160CAAGAGACAGGU 2161 AD-39815.1, AD-39803.1, AD- 39821.1, AD-39809.1,AD-39792.1, AD- 39780.1, AD-39798.1, AD-39786.1 CCUGUCUCUUGG 2162CCAAGAGACAGG 2163 AD-39815.1, AD-39821.1, AD- 39809.1, AD-39792.1,AD-39804.1, AD- 39780.1, AD-39798.1, AD-39786.1 CUGUCUCUUGGA 2164UCCAAGAGACAG 2165 AD-39815.1, AD-39821.1, AD- 39792.1, AD-39804.1,AD-39810.1, AD- 39780.1, AD-39798.1, AD-39786.1 UGUCUCUUGGAU 2166AUCCAAGAGACA 2167 AD-39816.1, AD-39821.1, AD- 39792.1, AD-39804.1,AD-39810.1, AD- 39780.1, AD-39798.1, AD-39786.1 GUCUCUUGGAUA 2168UAUCCAAGAGAC 2169 AD-39816.1, AD-39792.1, AD- 39804.1, AD-39810.1,AD-39780.1, AD- 39822.1, AD-39798.1, AD-39786.1 UCUCUUGGAUAU 2170AUAUCCAAGAGA 2171 AD-39816.1, AD-39792.1, AD- 39804.1, AD-39810.1,AD-39781.1, AD- 39822.1, AD-39798.1, AD-39786.1 CUCUUGGAUAUU 2172AAUAUCCAAGAG 2173 AD-39816.1, AD-39792.1, AD- 39804.1, AD-39787.1,AD-39810.1, AD- 39781.1, AD-39822.1, AD-39798.1 UCUUGGAUAUUC 2174GAAUAUCCAAGA 2175 AD-39816.1, AD-39793.1, AD- 39804.1, AD-39787.1,AD-39810.1, AD- 39781.1, AD-39822.1, AD-39798.1 CUUGGAUAUUCU 2176AGAAUAUCCAAG 2177 AD-39799.1, AD-39816.1, AD- 39793.1, AD-39804.1,AD-39787.1, AD- 39810.1, AD-39781.1, AD-39822.1 UUGGAUAUUCUC 2178GAGAAUAUCCAA 2179 AD-39799.1, AD-39816.1, AD- 39793.1, AD-39787.1,AD-35539.4, AD- 39810.1, AD-39781.1, AD-39822.1 UGGAUAUUCUCG 2180CGAGAAUAUCCA 2181 AD-39799.1, AD-39816.1, AD- 39793.1, AD-39787.1,AD-35539.4, AD- 35545.4, AD-39781.1, AD-39822.1 GGAUAUUCUCGA 2182UCGAGAAUAUCC 2183 AD-39799.1, AD-35551.4, AD- 39793.1, AD-39787.1,AD-35539.4, AD- 35545.4, AD-39781.1, AD-39822.1 GAUAUUCUCGAC 2184GUCGAGAAUAUC 2185 AD-39799.1, AD-35551.4, AD- 39793.1, AD-35557.1,AD-39787.1, AD- 35539.4, AD-35545.4, AD-39781.1 AUAUUCUCGACA 2186UGUCGAGAAUAU 2187 AD-39799.1, AD-35551.4, AD- 39793.1, AD-35557.1,AD-39787.1, AD- 35539.4, AD-35545.4, AD-35563.4 UAUUCUCGACAC 2188GUGUCGAGAAUA 2189 AD-39799.1, AD-35551.4, AD- 39793.1, AD-35557.1,AD-35539.4, AD- 35545.4, AD-35569.1, AD-35563.4 AUUCUCGACACA 2190UGUGUCGAGAAU 2191 AD-39799.1, AD-35528.4, AD- 35551.4, AD-35557.1,AD-35539.4, AD- 35545.4, AD-35569.1, AD-35563.4 UUCUCGACACAG 2192CUGUGUCGAGAA 2193 AD-35528.4, AD-35551.4, AD- 35557.1, AD-35539.4,AD-35534.1, AD- 35545.4, AD-35569.1, AD-35563.4 UCUCGACACAGC 2194GCUGUGUCGAGA 2195 AD-35528.4, AD-35551.4, AD- 35557.1, AD-35540.4,AD-35534.1, AD- 35545.4, AD-35569.1, AD-35563.4 CUCGACACAGCA 2196UGCUGUGUCGAG 2197 AD-35528.4, AD-35551.4, AD- 35546.4, AD-35557.1,AD-35540.4, AD- 35534.1, AD-35569.1, AD-35563.4 UCGACACAGCAG 2198CUGCUGUGUCGA 2199 AD-35552.4, AD-35528.4, AD- 35546.4, AD-35557.1,AD-35540.4, AD- 35534.1, AD-35569.1, AD-35563.4 CGACACAGCAGG 2200CCUGCUGUGUCG 2201 AD-35552.4, AD-35528.4, AD- 35558.4, AD-35546.4,AD-35540.4, AD- 35534.1, AD-35569.1, AD-35563.4 GACACAGCAGGU 2202ACCUGCUGUGUC 2203 AD-35552.4, AD-35528.4, AD- 35558.4, AD-35546.4,AD-35540.4, AD- 35534.1, AD-35564.4, AD-35569.1 ACACAGCAGGUC 2204GACCUGCUGUGU 2205 AD-35552.4, AD-35528.4, AD- 35558.4, AD-35546.4,AD-35540.4, AD- 35570.4, AD-35534.1, AD-35564.4 CACAGCAGGUCA 2206UGACCUGCUGUG 2207 AD-35552.4, AD-35558.4, AD- 35546.4, AD-35540.4,AD-35570.4, AD- 35534.1, AD-35564.4, AD-35571.4 ACAGCAGGUCAA 2208UUGACCUGCUGU 2209 AD-35577.4, AD-35552.4, AD- 35558.4, AD-35546.4,AD-35540.4, AD- 35570.4, AD-35564.4, AD-35571.4 CAGCAGGUCAAG 2210CUUGACCUGCUG 2211 AD-35577.4, AD-35552.4, AD- 35558.4, AD-35546.4,AD-35583.4, AD- 35570.4, AD-35564.4, AD-35571.4 AGCAGGUCAAGA 2212UCUUGACCUGCU 2213 AD-35577.4, AD-35552.4, AD- 35558.4, AD-35583.4,AD-35570.4, AD- 35564.4, AD-35589.4, AD-35571.4 GCAGGUCAAGAG 2214CUCUUGACCUGC 2215 AD-35577.4, AD-35595.4, AD- 35558.4, AD-35583.4,AD-35570.4, AD- 35564.4, AD-35589.4, AD-35571.4 CAGGUCAAGAGG 2216CCUCUUGACCUG 2217 AD-35577.4, AD-35595.4, AD- 35583.4, AD-35570.4,AD-35564.4, AD- 35589.4, AD-35571.4, AD-35601.4 AGGUCAAGAGGA 2218UCCUCUUGACCU 2219 AD-35577.4, AD-35595.4, AD- 35583.4, AD-35570.4,AD-35589.4, AD- 35607.4, AD-35571.4, AD-35601.4 GGUCAAGAGGAG 2220CUCCUCUUGACC 2221 AD-35577.4, AD-35595.4, AD- 35583.4, AD-35589.4,AD-35607.4, AD- 35571.4, AD-35613.4, AD-35601.4 GUCAAGAGGAGU 2222ACUCCUCUUGAC 2223 AD-35577.4, AD-35595.4, AD- 35583.4, AD-35572.4,AD-35589.4, AD- 35607.4, AD-35613.4, AD-35601.4 UCAAGAGGAGUA 2224UACUCCUCUUGA 2225 AD-35595.4, AD-35583.4, AD- 35578.4, AD-35572.4,AD-35589.4, AD- 35607.4, AD-35613.4, AD-35601.4 CAAGAGGAGUAC 2226GUACUCCUCUUG 2227 AD-35595.4, AD-35578.4, AD- 35572.4, AD-35584.4,AD-35589.4, AD- 35607.4, AD-35613.4, AD-35601.4 AAGAGGAGUACA 2228UGUACUCCUCUU 2229 AD-35590.4, AD-35595.4, AD- 35578.4, AD-35572.4,AD-35584.4, AD- 35607.4, AD-35613.4, AD-35601.4 AGAGGAGUACAG 2230CUGUACUCCUCU 2231 AD-35596.4, AD-35590.4, AD- 35578.4, AD-35572.4,AD-35584.4, AD- 35607.4, AD-35613.4, AD-35601.4 GAGGAGUACAGU 2232ACUGUACUCCUC 2233 AD-35596.4, AD-35590.4, AD- 35578.4, AD-35572.4,AD-35602.4, AD- 35584.4, AD-35607.4, AD-35613.4 AGGAGUACAGUG 2234CACUGUACUCCU 2235 AD-35608.4, AD-35596.4, AD- 35590.4, AD-35578.4,AD-35572.4, AD- 35602.4, AD-35584.4, AD-35613.4 GGAGUACAGUGC 2236GCACUGUACUCC 2237 AD-35608.4, AD-35596.4, AD- 35590.4, AD-35578.4,AD-35572.4, AD- 35614.4, AD-35602.4, AD-35584.4 GAGUACAGUGCA 2238UGCACUGUACUC 2239 AD-35608.4, AD-35596.4, AD- 35590.4, AD-35578.4,AD-35614.4, AD- 35602.4, AD-35584.4, AD-35573.4 AGUACAGUGCAA 2240UUGCACUGUACU 2241 AD-39805.1, AD-35608.4, AD- 35596.4, AD-35590.4,AD-35614.4, AD- 35602.4, AD-35584.4, AD-35573.4 GUACAGUGCAAU 2242AUUGCACUGUAC 2243 AD-39805.1, AD-35608.4, AD- 35596.4, AD-35590.4,AD-39811.1, AD- 35614.4, AD-35602.4, AD-35573.4 UACAGUGCAAUG 2244CAUUGCACUGUA 2245 AD-39805.1, AD-35608.4, AD- 35596.4, AD-39817.1,AD-39811.1, AD- 35614.4, AD-35602.4, AD-35573.4 ACAGUGCAAUGA 2246UCAUUGCACUGU 2247 AD-39805.1, AD-35608.4, AD- 39823.1, AD-39817.1,AD-39811.1, AD- 35614.4, AD-35602.4, AD-35573.4 CAGUGCAAUGAG 2248CUCAUUGCACUG 2249 AD-39805.1, AD-35608.4, AD- 39823.1, AD-39817.1,AD-39811.1, AD- 35614.4, AD-35573.4, AD-39782.1 AGUGCAAUGAGG 2250CCUCAUUGCACU 2251 AD-39805.1, AD-39823.1, AD- 39817.1, AD-39788.1,AD-39811.1, AD- 35614.4, AD-35573.4, AD-39782.1 GUGCAAUGAGGG 2252CCCUCAUUGCAC 2253 AD-39805.1, AD-39823.1, AD- 39817.1, AD-39788.1,AD-39811.1, AD- 35573.4, AD-39782.1, AD-39794.1 UGCAAUGAGGGA 2254UCCCUCAUUGCA 2255 AD-39805.1, AD-39823.1, AD- 39817.1, AD-39788.1,AD-39811.1, AD- 39782.1, AD-39794.1, AD-39800.1 GCAAUGAGGGAC 2256GUCCCUCAUUGC 2257 AD-39806.1, AD-39823.1, AD- 39817.1, AD-39788.1,AD-39811.1, AD- 39782.1, AD-39794.1, AD-39800.1 CAAUGAGGGACC 2258GGUCCCUCAUUG 2259 AD-39806.1, AD-39823.1, AD- 39812.1, AD-39817.1,AD-39788.1, AD- 39782.1, AD-39794.1, AD-39800.1 AAUGAGGGACCA 2260UGGUCCCUCAUU 2261 AD-39806.1, AD-39823.1, AD- 39812.1, AD-39788.1,AD-39782.1, AD- 39794.1, AD-39818.1, AD-39800.1 AUGAGGGACCAG 2262CUGGUCCCUCAU 2263 AD-39806.1, AD-39812.1, AD- 39788.1, AD-39824.1,AD-39782.1, AD- 39794.1, AD-39818.1, AD-39800.1 UGAGGGACCAGU 2264ACUGGUCCCUCA 2265 AD-39806.1, AD-39812.1, AD- 39788.1, AD-39824.1,AD-39783.1, AD- 39794.1, AD-39818.1, AD-39800.1 GAGGGACCAGUA 2266UACUGGUCCCUC 2267 AD-39789.1, AD-39806.1, AD- 39812.1, AD-39824.1,AD-39783.1, AD- 39794.1, AD-39818.1, AD-39800.1 AGGGACCAGUAC 2268GUACUGGUCCCU 2269 AD-39789.1, AD-39806.1, AD- 39812.1, AD-39824.1,AD-39795.1, AD- 39783.1, AD-39818.1, AD-39800.1 GGGACCAGUACA 2270UGUACUGGUCCC 2271 AD-39789.1, AD-39806.1, AD- 39812.1, AD-39824.1,AD-39795.1, AD- 39783.1, AD-39801.1, AD-39818.1 GGACCAGUACAU 2272AUGUACUGGUCC 2273 AD-39789.1, AD-39807.1, AD- 39812.1, AD-39824.1,AD-39795.1, AD- 39783.1, AD-39801.1, AD-39818.1 GACCAGUACAUG 2274CAUGUACUGGUC 2275 AD-39789.1, AD-39807.1, AD- 39824.1, AD-39795.1,AD-39783.1, AD- 39801.1, AD-39813.1, AD-39818.1 ACCAGUACAUGA 2276UCAUGUACUGGU 2277 AD-39789.1, AD-39807.1, AD- 39824.1, AD-39795.1,AD-39783.1, AD- 39801.1, AD-39813.1, AD-39819.1 CCAGUACAUGAG 2278CUCAUGUACUGG 2279 AD-39789.1, AD-39807.1, AD- 39795.1, AD-39783.1,AD-39801.1, AD- 39813.1, AD-39825.1, AD-39819.1 CAGUACAUGAGG 2280CCUCAUGUACUG 2281 AD-39789.1, AD-39807.1, AD- 39795.1, AD-39801.1,AD-39813.1, AD- 39825.1, AD-39831.1, AD-39819.1 AGUACAUGAGGA 2282UCCUCAUGUACU 2283 AD-39807.1, AD-39837.1, AD- 39795.1, AD-39801.1,AD-39813.1, AD- 39825.1, AD-39831.1, AD-39819.1 GUACAUGAGGAC 2284GUCCUCAUGUAC 2285 AD-39807.1, AD-39837.1, AD- 39843.1, AD-39801.1,AD-39813.1, AD- 39825.1, AD-39831.1, AD-39819.1 UACAUGAGGACU 2286AGUCCUCAUGUA 2287 AD-39807.1, AD-39837.1, AD- 39843.1, AD-39813.1,AD-39825.1, AD- 39831.1, AD-39849.1, AD-39819.1 ACAUGAGGACUG 2288CAGUCCUCAUGU 2289 AD-39837.1, AD-39843.1, AD- 39813.1, AD-39825.1,AD-39855.1, AD- 39831.1, AD-39849.1, AD-39819.1 CAUGAGGACUGG 2290CCAGUCCUCAUG 2291 AD-39861.1, AD-39837.1, AD- 39843.1, AD-39825.1,AD-39855.1, AD- 39831.1, AD-39849.1, AD-39819.1 AUGAGGACUGGG 2292CCCAGUCCUCAU 2293 AD-39861.1, AD-39837.1, AD- 39843.1, AD-39825.1,AD-39855.1, AD- 39831.1, AD-39867.1, AD-39849.1 UGAGGACUGGGG 2294CCCCAGUCCUCA 2295 AD-39861.1, AD-39837.1, AD- 39843.1, AD-39826.1,AD-39855.1, AD- 39831.1, AD-39867.1, AD-39849.1 GAGGACUGGGGA 2296UCCCCAGUCCUC 2297 AD-39861.1, AD-39832.1, AD- 39837.1, AD-39843.1,AD-39826.1, AD- 39855.1, AD-39867.1, AD-39849.1 AGGACUGGGGAG 2298CUCCCCAGUCCU 2299 AD-39861.1, AD-39832.1, AD- 39843.1, AD-39826.1,AD-39855.1, AD- 39867.1, AD-39849.1, AD-39838.1 GGACUGGGGAGG 2300CCUCCCCAGUCC 2301 AD-39844.1, AD-39861.1, AD- 39832.1, AD-39826.1,AD-39855.1, AD- 39867.1, AD-39849.1, AD-39838.1 GACUGGGGAGGG 2302CCCUCCCCAGUC 2303 AD-39850.1, AD-39844.1, AD- 39861.1, AD-39832.1,AD-39826.1, AD- 39855.1, AD-39867.1, AD-39838.1 ACUGGGGAGGGC 2304GCCCUCCCCAGU 2305 AD-39850.1, AD-39844.1, AD- 39861.1, AD-39832.1,AD-39856.1, AD- 39826.1, AD-39867.1, AD-39838.1 CUGGGGAGGGCU 2306AGCCCUCCCCAG 2307 AD-39850.1, AD-39844.1, AD- 39862.1, AD-39832.1,AD-39856.1, AD- 39826.1, AD-39867.1, AD-39838.1 UGGGGAGGGCUU 2308AAGCCCUCCCCA 2309 AD-39850.1, AD-39844.1, AD- 39868.1, AD-39862.1,AD-39832.1, AD- 39856.1, AD-39826.1, AD-39838.1 GGGGAGGGCUUU 2310AAAGCCCUCCCC 2311 AD-39850.1, AD-39844.1, AD- 39868.1, AD-35579.4,AD-39862.1, AD- 39832.1, AD-39856.1, AD-39838.1 GGGAGGGCUUUC 2312GAAAGCCCUCCC 2313 AD-35585.4, AD-39850.1, AD- 39844.1, AD-39868.1,AD-35579.4, AD- 39862.1, AD-39856.1, AD-39838.1 GGAGGGCUUUCU 2314AGAAAGCCCUCC 2315 AD-35585.4, AD-39850.1, AD- 39844.1, AD-39868.1,AD-35579.4, AD- 39862.1, AD-39856.1, AD-35591.4 GAGGGCUUUCUU 2316AAGAAAGCCCUC 2317 AD-35585.4, AD-39850.1, AD- 39868.1, AD-35579.4,AD-39862.1, AD- 35597.4, AD-39856.1, AD-35591.4 AGGGCUUUCUUU 2318AAAGAAAGCCCU 2319 AD-35585.4, AD-39868.1, AD- 35579.4, AD-39862.1,AD-35597.4, AD- 39856.1, AD-35591.4, AD-35603.4 GGGCUUUCUUUG 2320CAAAGAAAGCCC 2321 AD-35585.4, AD-39868.1, AD- 35579.4, AD-39862.1,AD-35597.4, AD- 35609.4, AD-35591.4, AD-35603.4 GGCUUUCUUUGU 2322ACAAAGAAAGCC 2323 AD-35585.4, AD-39868.1, AD- 35579.4, AD-35615.4,AD-35597.4, AD- 35609.4, AD-35591.4, AD-35603.4 GCUUUCUUUGUG 2324CACAAAGAAAGC 2325 AD-35585.4, AD-35579.4, AD- 35615.4, AD-35597.4,AD-35609.4, AD- 35591.4, AD-35603.4, AD-35574.4 CUUUCUUUGUGU 2326ACACAAAGAAAG 2327 AD-35585.4, AD-35615.4, AD- 35597.4, AD-35609.4,AD-35591.4, AD- 35603.4, AD-35580.1, AD-35574.4 UUUCUUUGUGUA 2328UACACAAAGAAA 2329 AD-35615.4, AD-35597.4, AD- 35609.4, AD-35591.4,AD-35603.4, AD- 35586.4, AD-35580.1, AD-35574.4 UUCUUUGUGUAU 2330AUACACAAAGAA 2331 AD-35615.4, AD-35597.4, AD- 35609.4, AD-35592.4,AD-35603.4, AD- 35586.4, AD-35580.1, AD-35574.4 UCUUUGUGUAUU 2332AAUACACAAAGA 2333 AD-35615.4, AD-35609.4, AD- 35592.4, AD-35603.4,AD-35586.4, AD- 35598.4, AD-35580.1, AD-35574.4 CUUUGUGUAUUU 2334AAAUACACAAAG 2335 AD-35604.4, AD-35615.4, AD- 35609.4, AD-35592.4,AD-35586.4, AD- 35598.4, AD-35580.1, AD-35574.4 UUUGUGUAUUUG 2336CAAAUACACAAA 2337 AD-35604.4, AD-35615.4, AD- 35592.4, AD-35586.4,AD-35610.4, AD- 35598.4, AD-35580.1, AD-35574.4 UUGUGUAUUUGC 2338GCAAAUACACAA 2339 AD-35604.4, AD-35592.4, AD- 35586.4, AD-35610.4,AD-35598.4, AD- 35616.4, AD-35580.1, AD-35574.4 UGUGUAUUUGCC 2340GGCAAAUACACA 2341 AD-35604.4, AD-35575.4, AD- 35592.4, AD-35586.4,AD-35610.4, AD- 35598.4, AD-35616.4, AD-35580.1 GUGUAUUUGCCA 2342UGGCAAAUACAC 2343 AD-35604.4, AD-35575.4, AD- 35581.4, AD-35592.4,AD-35586.4, AD- 35610.4, AD-35598.4, AD-35616.4 UGUAUUUGCCAU 2344AUGGCAAAUACA 2345 AD-35604.4, AD-35575.4, AD- 35581.4, AD-35592.4,AD-35587.4, AD- 35610.4, AD-35598.4, AD-35616.4 GUAUUUGCCAUA 2346UAUGGCAAAUAC 2347 AD-35604.4, AD-35575.4, AD- 35581.4, AD-35587.4,AD-35610.4, AD- 35598.4, AD-35616.4, AD-35593.4 UAUUUGCCAUAA 2348UUAUGGCAAAUA 2349 AD-35604.4, AD-35575.4, AD- 35581.4, AD-35587.4,AD-35610.4, AD- 35616.4, AD-35593.4, AD-35599.4 AUUUGCCAUAAA 2350UUUAUGGCAAAU 2351 AD-35575.4, AD-35581.4, AD- 35587.4, AD-35610.4,AD-35605.4, AD- 35616.4, AD-35593.4, AD-35599.4 UUUGCCAUAAAU 2352AUUUAUGGCAAA 2353 AD-35611.4, AD-35575.4, AD- 35581.4, AD-35587.4,AD-35605.4, AD- 35616.4, AD-35593.4, AD-35599.4 UUGCCAUAAAUA 2354UAUUUAUGGCAA 2355 AD-35611.4, AD-35575.4, AD- 35581.4, AD-35587.4,AD-35605.4, AD- 35593.4, AD-39827.1, AD-35599.4 UGCCAUAAAUAA 2356UUAUUUAUGGCA 2357 AD-35611.4, AD-35581.4, AD- 35587.4, AD-39833.1,AD-35605.4, AD- 35593.4, AD-39827.1, AD-35599.4 GCCAUAAAUAAU 2358AUUAUUUAUGGC 2359 AD-39839.1, AD-35611.4, AD- 35587.4, AD-39833.1,AD-35605.4, AD- 35593.4, AD-39827.1, AD-35599.4 CCAUAAAUAAUA 2360UAUUAUUUAUGG 2361 AD-39839.1, AD-35611.4, AD- 39833.1, AD-35605.4,AD-35593.4, AD- 39827.1, AD-35599.4, AD-39845.1 CAUAAAUAAUAC 2362GUAUUAUUUAUG 2363 AD-39839.1, AD-35611.4, AD- 39833.1, AD-35605.4,AD-39851.1, AD- 39827.1, AD-35599.4, AD-39845.1 AUAAAUAAUACU 2364AGUAUUAUUUAU 2365 AD-39839.1, AD-35611.4, AD- 39857.1, AD-39833.1,AD-35605.4, AD- 39851.1, AD-39827.1, AD-39845.1 UAAAUAAUACUA 2366UAGUAUUAUUUA 2367 AD-39839.1, AD-35611.4, AD- 39857.1, AD-39833.1,AD-39851.1, AD- 39863.1, AD-39827.1, AD-39845.1 AAAUAAUACUAA 2368UUAGUAUUAUUU 2369 AD-39839.1, AD-39857.1, AD- 39869.1, AD-39833.1,AD-39851.1, AD- 39863.1, AD-39827.1, AD-39845.1 AAUAAUACUAAA 2370UUUAGUAUUAUU 2371 AD-39828.1, AD-39839.1, AD- 39857.1, AD-39869.1,AD-39833.1, AD- 39851.1, AD-39863.1, AD-39845.1 AUAAUACUAAAU 2372AUUUAGUAUUAU 2373 AD-39828.1, AD-39839.1, AD- 39857.1, AD-39834.1,AD-39869.1, AD- 39851.1, AD-39863.1, AD-39845.1 UAAUACUAAAUC 2374GAUUUAGUAUUA 2375 AD-39828.1, AD-39857.1, AD- 39834.1, AD-39869.1,AD-39840.1, AD- 39851.1, AD-39863.1, AD-39845.1 AAUACUAAAUCA 2376UGAUUUAGUAUU 2377 AD-39828.1, AD-39857.1, AD- 39834.1, AD-39869.1,AD-39840.1, AD- 39851.1, AD-39863.1, AD-39846.1 AUACUAAAUCAU 2378AUGAUUUAGUAU 2379 AD-39828.1, AD-39852.1, AD- 39857.1, AD-39834.1,AD-39869.1, AD- 39840.1, AD-39863.1, AD-39846.1 UACUAAAUCAUU 2380AAUGAUUUAGUA 2381 AD-39828.1, AD-39852.1, AD- 39834.1, AD-39858.1,AD-39869.1, AD- 39840.1, AD-39863.1, AD-39846.1 ACUAAAUCAUUU 2382AAAUGAUUUAGU 2383 AD-39828.1, AD-39852.1, AD- 39834.1, AD-39858.1,AD-39869.1, AD- 39840.1, AD-39864.1, AD-39846.1 CUAAAUCAUUUG 2384CAAAUGAUUUAG 2385 AD-39828.1, AD-39852.1, AD- 39870.1, AD-39834.1,AD-39858.1, AD- 39840.1, AD-39864.1, AD-39846.1 UAAAUCAUUUGA 2386UCAAAUGAUUUA 2387 AD-39852.1, AD-39870.1, AD- 39829.1, AD-39834.1,AD-39858.1, AD- 39840.1, AD-39864.1, AD-39846.1 AAAUCAUUUGAA 2388UUCAAAUGAUUU 2389 AD-39852.1, AD-39870.1, AD- 39829.1, AD-39858.1,AD-39840.1, AD- 39835.1, AD-39864.1, AD-39846.1 AAUCAUUUGAAG 2390CUUCAAAUGAUU 2391 AD-39852.1, AD-39870.1, AD- 39841.1, AD-39829.1,AD-39858.1, AD- 39835.1, AD-39864.1, AD-39846.1 AUCAUUUGAAGA 2392UCUUCAAAUGAU 2393 AD-39852.1, AD-39870.1, AD- 39841.1, AD-39829.1,AD-39858.1, AD- 39835.1, AD-39864.1 UCAUUUGAAGAU 2394 AUCUUCAAAUGA 2395AD-39870.1, AD-39841.1, AD- 39829.1, AD-39858.1, AD-39835.1, AD-39864.1, AD-39853.1 CAUUUGAAGAUA 2396 UAUCUUCAAAUG 2397 AD-39870.1,AD-39841.1, AD- 39829.1, AD-39835.1, AD-39859.1, AD- 39864.1, AD-39853.1AUUUGAAGAUAU 2398 AUAUCUUCAAAU 2399 AD-39865.1, AD-39870.1, AD- 39841.1,AD-39829.1, AD-39835.1, AD- 39859.1, AD-39853.1 UUUGAAGAUAUU 2400AAUAUCUUCAAA 2401 AD-39871.1, AD-39865.1, AD- 39841.1, AD-39829.1,AD-39835.1, AD- 39859.1, AD-39853.1 UUGAAGAUAUUC 2402 GAAUAUCUUCAA 2403AD-39871.1, AD-39865.1, AD- 39841.1, AD-39830.1, AD-39835.1, AD-39859.1, AD-39853.1 UGAAGAUAUUCA 2404 UGAAUAUCUUCA 2405 AD-39871.1,AD-39865.1, AD- 39841.1, AD-39830.1, AD-35617.4, AD- 39859.1, AD-39853.1GAAGAUAUUCAC 2406 GUGAAUAUCUUC 2407 AD-39871.1, AD-39865.1, AD- 39830.1,AD-35617.4, AD-35576.4, AD- 39859.1, AD-39853.1 AAGAUAUUCACC 2408GGUGAAUAUCUU 2409 AD-35582.1, AD-39871.1, AD- 39865.1, AD-39830.1,AD-35617.4, AD- 35576.4, AD-39859.1, AD-39853.1 AGAUAUUCACCA 2410UGGUGAAUAUCU 2411 AD-35582.1, AD-39871.1, AD- 39865.1, AD-39830.1,AD-35617.4, AD- 35576.4, AD-39859.1, AD-35588.4 GAUAUUCACCAU 2412AUGGUGAAUAUC 2413 AD-35582.1, AD-39871.1, AD- 39865.1, AD-35594.1,AD-39830.1, AD- 35617.4, AD-35576.4, AD-35588.4 AUAUUCACCAUU 2414AAUGGUGAAUAU 2415 AD-35582.1, AD-39871.1, AD- 35594.1, AD-35600.1,AD-39830.1, AD- 35617.4, AD-35576.4, AD-35588.4 UAUUCACCAUUA 2416UAAUGGUGAAUA 2417 AD-35582.1, AD-35606.1, AD- 35594.1, AD-35600.1,AD-39830.1, AD- 35617.4, AD-35576.4, AD-35588.4 AUUCACCAUUAU 2418AUAAUGGUGAAU 2419 AD-35582.1, AD-35606.1, AD- 35594.1, AD-35612.1,AD-35600.1, AD- 35617.4, AD-35576.4, AD-35588.4 UUCACCAUUAUA 2420UAUAAUGGUGAA 2421 AD-35582.1, AD-35606.1, AD- 35594.1, AD-35612.1,AD-35600.1, AD- 35576.4, AD-35618.1, AD-35588.4 UCACCAUUAUAG 2422CUAUAAUGGUGA 2423 AD-35582.1, AD-35606.1, AD- 35594.1, AD-35612.1,AD-35600.1, AD- 35618.1, AD-35588.4, AD-38127.1 CACCAUUAUAGA 2424UCUAUAAUGGUG 2425 AD-38133.1, AD-35606.1, AD- 35594.1, AD-35612.1,AD-35600.1, AD- 35618.1, AD-35588.4, AD-38127.1 ACCAUUAUAGAG 2426CUCUAUAAUGGU 2427 AD-38133.1, AD-35606.1, AD- 35594.1, AD-35612.1,AD-35600.1, AD- 38139.1, AD-35618.1, AD-38127.1 CCAUUAUAGAGA 2428UCUCUAUAAUGG 2429 AD-38133.1, AD-35606.1, AD- 35612.1, AD-35600.1,AD-38145.1, AD- 38139.1, AD-35618.1, AD-38127.1 CAUUAUAGAGAA 2430UUCUCUAUAAUG 2431 AD-38133.1, AD-35606.1, AD- 35612.1, AD-38145.1,AD-38139.1, AD- 38151.1, AD-35618.1, AD-38127.1 AUUAUAGAGAAC 2432GUUCUCUAUAAU 2433 AD-38133.1, AD-35612.1, AD- 38145.1, AD-38139.1,AD-38151.1, AD- 38157.1, AD-35618.1, AD-38127.1 UUAUAGAGAACA 2434UGUUCUCUAUAA 2435 AD-38133.1, AD-38163.1, AD- 38145.1, AD-38139.1,AD-38151.1, AD- 38157.1, AD-35618.1, AD-38127.1 UAUAGAGAACAA 2436UUGUUCUCUAUA 2437 AD-38133.1, AD-38163.1, AD- 38145.1, AD-38169.1,AD-38139.1, AD- 38151.1, AD-38157.1, AD-38127.1 AUAGAGAACAAA 2438UUUGUUCUCUAU 2439 AD-38133.1, AD-38163.1, AD- 38145.1, AD-38169.1,AD-38139.1, AD- 38151.1, AD-38157.1, AD-38128.1 UAGAGAACAAAU 2440AUUUGUUCUCUA 2441 AD-38163.1, AD-38145.1, AD- 38169.1, AD-38139.1,AD-38151.1, AD- 38157.1, AD-38128.1, AD-38134.1 AGAGAACAAAUU 2442AAUUUGUUCUCU 2443 AD-38163.1, AD-38145.1, AD- 38140.1, AD-38169.1,AD-38151.1, AD- 38157.1, AD-38128.1, AD-38134.1 GAGAACAAAUUA 2444UAAUUUGUUCUC 2445 AD-38163.1, AD-38140.1, AD- 38169.1, AD-38151.1,AD-38157.1, AD- 38128.1, AD-39836.1, AD-38134.1 AGAACAAAUUAA 2446UUAAUUUGUUCU 2447 AD-38163.1, AD-38140.1, AD- 38169.1, AD-38157.1,AD-38128.1, AD- 39842.1, AD-39836.1, AD-38134.1 GAACAAAUUAAA 2448UUUAAUUUGUUC 2449 AD-38163.1, AD-38140.1, AD- 38169.1, AD-38128.1,AD-39842.1, AD- 39848.1, AD-39836.1, AD-38134.1 AACAAAUUAAAA 2450UUUUAAUUUGUU 2451 AD-38140.1, AD-38169.1, AD- 39854.1, AD-38128.1,AD-39842.1, AD- 39848.1, AD-39836.1, AD-38134.1 ACAAAUUAAAAG 2452CUUUUAAUUUGU 2453 AD-39860.1, AD-38140.1, AD- 39854.1, AD-38128.1,AD-39842.1, AD- 39848.1, AD-39836.1, AD-38134.1 CAAAUUAAAAGA 2454UCUUUUAAUUUG 2455 AD-39860.1, AD-38140.1, AD- 39854.1, AD-39842.1,AD-39848.1, AD- 39866.1, AD-39836.1, AD-38134.1 AAAUUAAAAGAG 2456CUCUUUUAAUUU 2457 AD-39992.1, AD-39860.1, AD- 38140.1, AD-39854.1,AD-39842.1, AD- 39848.1, AD-39866.1, AD-39836.1 AAUUAAAAGAGU 2458ACUCUUUUAAUU 2459 AD-39992.1, AD-39860.1, AD- 39998.1, AD-39854.1,AD-39842.1, AD- 39848.1, AD-39866.1, AD-39836.1 AUUAAAAGAGUU 2460AACUCUUUUAAU 2461 AD-39992.1, AD-39860.1, AD- 40004.1, AD-39998.1,AD-39854.1, AD- 39842.1, AD-39848.1, AD-39866.1 UUAAAAGAGUUA 2462UAACUCUUUUAA 2463 AD-39992.1, AD-39860.1, AD- 40004.1, AD-39998.1,AD-39854.1, AD- 40010.1, AD-39848.1, AD-39866.1 UAAAAGAGUUAA 2464UUAACUCUUUUA 2465 AD-40016.1, AD-39992.1, AD- 39860.1, AD-40004.1,AD-39998.1, AD- 39854.1, AD-40010.1, AD-39866.1 AAAAGAGUUAAG 2466CUUAACUCUUUU 2467 AD-40016.1, AD-39992.1, AD- 39860.1, AD-40022.1,AD-40004.1, AD- 39998.1, AD-40010.1, AD-39866.1 AAAGAGUUAAGG 2468CCUUAACUCUUU 2469 AD-40016.1, AD-40028.1, AD- 39992.1, AD-40022.1,AD-40004.1, AD- 39998.1, AD-40010.1, AD-39866.1 AAGAGUUAAGGA 2470UCCUUAACUCUU 2471 AD-40016.1, AD-40028.1, AD- 40034.1, AD-39992.1,AD-40022.1, AD- 40004.1, AD-39998.1, AD-40010.1 AGAGUUAAGGAC 2472GUCCUUAACUCU 2473 AD-40016.1, AD-40028.1, AD- 40034.1, AD-40022.1,AD-40004.1, AD- 39998.1, AD-40010.1 GAGUUAAGGACU 2474 AGUCCUUAACUC 2475AD-40016.1, AD-40028.1, AD- 40034.1, AD-39999.1, AD-40022.1, AD-40004.1, AD-40010.1 AGUUAAGGACUC 2476 GAGUCCUUAACU 2477 AD-40016.1,AD-40028.1, AD- 40034.1, AD-39999.1, AD-40022.1, AD- 40005.1, AD-40010.1GUUAAGGACUCU 2478 AGAGUCCUUAAC 2479 AD-40016.1, AD-40011.1, AD- 40028.1,AD-40034.1, AD-39999.1, AD- 40022.1, AD-40005.1 UUAAGGACUCUG 2480CAGAGUCCUUAA 2481 AD-40017.1, AD-40011.1, AD- 40028.1, AD-40034.1,AD-39999.1, AD- 40022.1, AD-40005.1 UAAGGACUCUGA 2482 UCAGAGUCCUUA 2483AD-40017.1, AD-40011.1, AD- 40028.1, AD-40034.1, AD-39999.1, AD- 40005.1AAGGACUCUGAA 2484 UUCAGAGUCCUU 2485 AD-40017.1, AD-40029.1, AD- 40011.1,AD-40034.1, AD-39999.1, AD- 40005.1 AGGACUCUGAAG 2486 CUUCAGAGUCCU 2487AD-40017.1, AD-40029.1, AD- 40011.1, AD-39999.1, AD-40005.1, AD- 40035.1GGACUCUGAAGA 2488 UCUUCAGAGUCC 2489 AD-40017.1, AD-40029.1, AD- 40011.1,AD-39994.1, AD-39999.1, AD- 40005.1, AD-40035.1 GACUCUGAAGAU 2490AUCUUCAGAGUC 2491 AD-40017.1, AD-40029.1, AD- 40011.1, AD-40000.1,AD-39994.1, AD- 40005.1, AD-40035.1 ACUCUGAAGAUG 2492 CAUCUUCAGAGU 2493AD-40017.1, AD-40029.1, AD- 40011.1, AD-40000.1, AD-39994.1, AD-40006.1, AD-40035.1 CUCUGAAGAUGU 2494 ACAUCUUCAGAG 2495 AD-40017.1,AD-40029.1, AD- 40000.1, AD-39994.1, AD-40012.1, AD- 40006.1, AD-40035.1UCUGAAGAUGUA 2496 UACAUCUUCAGA 2497 AD-40029.1, AD-40000.1, AD- 39994.1,AD-40012.1, AD-40006.1, AD- 40035.1, AD-40018.1 CUGAAGAUGUAC 2498GUACAUCUUCAG 2499 AD-40029.1, AD-40000.1, AD- 39994.1, AD-40024.1,AD-40012.1, AD- 40006.1, AD-40035.1, AD-40018.1 UGAAGAUGUACC 2500GGUACAUCUUCA 2501 AD-40030.1, AD-40000.1, AD- 39994.1, AD-40024.1,AD-40012.1, AD- 40006.1, AD-40035.1, AD-40018.1 GAAGAUGUACCU 2502AGGUACAUCUUC 2503 AD-40030.1, AD-40000.1, AD- 39994.1, AD-40024.1,AD-40012.1, AD- 40006.1, AD-38146.1, AD-40018.1 AAGAUGUACCUA 2504UAGGUACAUCUU 2505 AD-40030.1, AD-40000.1, AD- 40024.1, AD-40012.1,AD-40006.1, AD- 38146.1, AD-40018.1, AD-38152.1 AGAUGUACCUAU 2506AUAGGUACAUCU 2507 AD-40030.1, AD-40024.1, AD- 40012.1, AD-40006.1,AD-38158.1, AD- 38146.1, AD-40018.1, AD-38152.1 GAUGUACCUAUG 2508CAUAGGUACAUC 2509 AD-40030.1, AD-40024.1, AD- 40012.1, AD-38164.1,AD-38158.1, AD- 38146.1, AD-40018.1, AD-38152.1 AUGUACCUAUGG 2510CCAUAGGUACAU 2511 AD-40030.1, AD-40024.1, AD- 38164.1, AD-38170.1,AD-38158.1, AD- 38146.1, AD-40018.1, AD-38152.1 UGUACCUAUGGU 2512ACCAUAGGUACA 2513 AD-40030.1, AD-40024.1, AD- 38164.1, AD-38129.1,AD-38170.1, AD- 38158.1, AD-38146.1, AD-38152.1 GUACCUAUGGUC 2514GACCAUAGGUAC 2515 AD-40030.1, AD-38164.1, AD- 38129.1, AD-38170.1,AD-38158.1, AD- 38146.1, AD-38152.1, AD-38135.1 UACCUAUGGUCC 2516GGACCAUAGGUA 2517 AD-38164.1, AD-38129.1, AD- 38170.1, AD-38158.1,AD-38146.1, AD- 38141.1, AD-38152.1, AD-38135.1 ACCUAUGGUCCU 2518AGGACCAUAGGU 2519 AD-38164.1, AD-38129.1, AD- 38170.1, AD-38147.1,AD-38158.1, AD- 38141.1, AD-38152.1, AD-38135.1 CCUAUGGUCCUA 2520UAGGACCAUAGG 2521 AD-38164.1, AD-38129.1, AD- 38153.1, AD-38170.1,AD-38147.1, AD- 38158.1, AD-38141.1, AD-38135.1 CUAUGGUCCUAG 2522CUAGGACCAUAG 2523 AD-38164.1, AD-38159.1, AD- 38129.1, AD-38153.1,AD-38170.1, AD- 38147.1, AD-38141.1, AD-38135.1 UAUGGUCCUAGU 2524ACUAGGACCAUA 2525 AD-38165.1, AD-38159.1, AD- 38129.1, AD-38153.1,AD-38170.1, AD- 38147.1, AD-38141.1, AD-38135.1 AUGGUCCUAGUA 2526UACUAGGACCAU 2527 AD-38165.1, AD-38171.1, AD- 38159.1, AD-38129.1,AD-38153.1, AD- 38147.1, AD-38141.1, AD-38135.1 UGGUCCUAGUAG 2528CUACUAGGACCA 2529 AD-38165.1, AD-38171.1, AD- 38159.1, AD-38153.1,AD-38147.1, AD- 38141.1, AD-38130.1, AD-38135.1 GGUCCUAGUAGG 2530CCUACUAGGACC 2531 AD-38165.1, AD-38171.1, AD- 38159.1, AD-38136.1,AD-38153.1, AD- 38147.1, AD-38141.1, AD-38130.1 GUCCUAGUAGGA 2532UCCUACUAGGAC 2533 AD-38165.1, AD-38171.1, AD- 38159.1, AD-38136.1,AD-38153.1, AD- 38147.1, AD-38142.1, AD-38130.1 UCCUAGUAGGAA 2534UUCCUACUAGGA 2535 AD-38165.1, AD-38171.1, AD- 38159.1, AD-38136.1,AD-38148.1, AD- 38153.1, AD-38142.1, AD-38130.1 CCUAGUAGGAAA 2536UUUCCUACUAGG 2537 AD-38165.1, AD-38171.1, AD- 38154.1, AD-38159.1,AD-38136.1, AD- 38148.1, AD-38142.1, AD-38130.1 CUAGUAGGAAAU 2538AUUUCCUACUAG 2539 AD-38165.1, AD-38171.1, AD- 38154.1, AD-38136.1,AD-38148.1, AD- 38160.1, AD-38142.1, AD-38130.1 UAGUAGGAAAUA 2540UAUUUCCUACUA 2541 AD-38171.1, AD-38154.1, AD- 38136.1, AD-38148.1,AD-38166.1, AD- 38160.1, AD-38142.1, AD-38130.1 AGUAGGAAAUAA 2542UUAUUUCCUACU 2543 AD-38154.1, AD-38136.1, AD- 38148.1, AD-38172.1,AD-38166.1, AD- 38160.1, AD-38142.1, AD-38130.1 GUAGGAAAUAAA 2544UUUAUUUCCUAC 2545 AD-40036.1, AD-38154.1, AD- 38136.1, AD-38148.1,AD-38172.1, AD- 38166.1, AD-38160.1, AD-38142.1 UAGGAAAUAAAU 2546AUUUAUUUCCUA 2547 AD-39995.1, AD-40036.1, AD- 38154.1, AD-38148.1,AD-38172.1, AD- 38166.1, AD-38160.1, AD-38142.1 AGGAAAUAAAUG 2548CAUUUAUUUCCU 2549 AD-39995.1, AD-40036.1, AD- 38154.1, AD-40001.1,AD-38148.1, AD- 38172.1, AD-38166.1, AD-38160.1 GGAAAUAAAUGU 2550ACAUUUAUUUCC 2551 AD-39995.1, AD-40036.1, AD- 38154.1, AD-40001.1,AD-38172.1, AD- 38166.1, AD-38160.1, AD-40007.1 GAAAUAAAUGUG 2552CACAUUUAUUUC 2553 AD-39995.1, AD-40036.1, AD- 40013.1, AD-40001.1,AD-38172.1, AD- 38166.1, AD-38160.1, AD-40007.1 AAAUAAAUGUGA 2554UCACAUUUAUUU 2555 AD-39995.1, AD-40036.1, AD- 40013.1, AD-40001.1,AD-38172.1, AD- 38166.1, AD-40007.1, AD-40019.1 AAUAAAUGUGAU 2556AUCACAUUUAUU 2557 AD-39995.1, AD-40036.1, AD- 40013.1, AD-40001.1,AD-40025.1, AD- 38172.1, AD-40007.1, AD-40019.1 AUAAAUGUGAUU 2558AAUCACAUUUAU 2559 AD-39995.1, AD-40036.1, AD- 40013.1, AD-40001.1,AD-40025.1, AD- 40031.1, AD-40007.1, AD-40019.1 UAAAUGUGAUUU 2560AAAUCACAUUUA 2561 AD-39995.1, AD-40013.1, AD- 40037.1, AD-40001.1,AD-40025.1, AD- 40031.1, AD-40007.1, AD-40019.1 AAAUGUGAUUUG 2562CAAAUCACAUUU 2563 AD-40013.1, AD-40037.1, AD- 40001.1, AD-40025.1,AD-40031.1, AD- 40007.1, AD-39996.1, AD-40019.1 AAUGUGAUUUGC 2564GCAAAUCACAUU 2565 AD-40013.1, AD-40037.1, AD- 40025.1, AD-40031.1,AD-40002.1, AD- 40007.1, AD-39996.1, AD-40019.1 AUGUGAUUUGCC 2566GGCAAAUCACAU 2567 AD-40008.1, AD-40013.1, AD- 40037.1, AD-40025.1,AD-40031.1, AD- 40002.1, AD-39996.1, AD-40019.1 UGUGAUUUGCCU 2568AGGCAAAUCACA 2569 AD-40008.1, AD-40037.1, AD- 40025.1, AD-40031.1,AD-40002.1, AD- 40014.1, AD-39996.1, AD-40019.1 GUGAUUUGCCUU 2570AAGGCAAAUCAC 2571 AD-40008.1, AD-40037.1, AD- 40020.1, AD-40025.1,AD-40031.1, AD- 40002.1, AD-40014.1, AD-39996.1 UGAUUUGCCUUC 2572GAAGGCAAAUCA 2573 AD-40026.1, AD-40008.1, AD- 40037.1, AD-40020.1,AD-40031.1, AD- 40002.1, AD-40014.1, AD-39996.1 GAUUUGCCUUCU 2574AGAAGGCAAAUC 2575 AD-40026.1, AD-40008.1, AD- 40032.1, AD-40037.1,AD-40020.1, AD- 40002.1, AD-40014.1, AD-39996.1 AUUUGCCUUCUA 2576UAGAAGGCAAAU 2577 AD-40038.1, AD-40026.1, AD- 40008.1, AD-40032.1,AD-40020.1, AD- 40002.1, AD-40014.1, AD-39996.1 UUUGCCUUCUAG 2578CUAGAAGGCAAA 2579 AD-40038.1, AD-40026.1, AD- 40008.1, AD-40032.1,AD-40020.1, AD- 40002.1, AD-39997.1, AD-40014.1 UUGCCUUCUAGA 2580UCUAGAAGGCAA 2581 AD-40038.1, AD-40026.1, AD- 40008.1, AD-40032.1,AD-40020.1, AD- 39997.1, AD-40014.1 UGCCUUCUAGAA 2582 UUCUAGAAGGCA 2583AD-40038.1, AD-40026.1, AD- 40032.1, AD-40020.1, AD-40009.1, AD-39997.1, AD-40014.1 GCCUUCUAGAAC 2584 GUUCUAGAAGGC 2585 AD-40038.1,AD-40026.1, AD- 40015.1, AD-40032.1, AD-40020.1, AD- 40009.1, AD-39997.1CCUUCUAGAACA 2586 UGUUCUAGAAGG 2587 AD-40038.1, AD-40026.1, AD- 40015.1,AD-40021.1, AD-40032.1, AD- 40009.1, AD-39997.1 CUUCUAGAACAG 2588CUGUUCUAGAAG 2589 AD-40038.1, AD-40027.1, AD- 40015.1, AD-40021.1,AD-40032.1, AD- 40009.1, AD-39997.1 UUCUAGAACAGU 2590 ACUGUUCUAGAA 2591AD-40038.1, AD-40027.1, AD- 40015.1, AD-40021.1, AD-40009.1, AD-40033.1, AD-39997.1 UCUAGAACAGUA 2592 UACUGUUCUAGA 2593 AD-40027.1,AD-40015.1, AD- 40021.1, AD-40039.1, AD-40009.1, AD- 40033.1, AD-39997.1CUAGAACAGUAG 2594 CUACUGUUCUAG 2595 AD-40027.1, AD-40015.1, AD- 40021.1,AD-40039.1, AD-40009.1, AD- 40033.1, AD-40045.1 UAGAACAGUAGA 2596UCUACUGUUCUA 2597 AD-40027.1, AD-40015.1, AD- 40021.1, AD-40051.1,AD-40039.1, AD- 40009.1, AD-40033.1, AD-40045.1 AGAACAGUAGAC 2598GUCUACUGUUCU 2599 AD-40027.1, AD-40057.1, AD- 40015.1, AD-40021.1,AD-40051.1, AD- 40039.1, AD-40033.1, AD-40045.1 GAACAGUAGACA 2600UGUCUACUGUUC 2601 AD-40027.1, AD-40057.1, AD- 40021.1, AD-40051.1,AD-40039.1, AD- 40063.1, AD-40033.1, AD-40045.1 AACAGUAGACAC 2602GUGUCUACUGUU 2603 AD-40027.1, AD-40057.1, AD- 40051.1, AD-40039.1,AD-40063.1, AD- 40033.1, AD-40045.1, AD-40069.1 ACAGUAGACACA 2604UGUGUCUACUGU 2605 AD-40057.1, AD-40051.1, AD- 40075.1, AD-40039.1,AD-40063.1, AD- 40033.1, AD-40045.1, AD-40069.1 CAGUAGACACAA 2606UUGUGUCUACUG 2607 AD-40057.1, AD-40051.1, AD- 40075.1, AD-40039.1,AD-40081.1, AD- 40063.1, AD-40045.1, AD-40069.1 AGUAGACACAAA 2608UUUGUGUCUACU 2609 AD-40057.1, AD-40051.1, AD- 40075.1, AD-40040.1,AD-40081.1, AD- 40063.1, AD-40045.1, AD-40069.1 GUAGACACAAAA 2610UUUUGUGUCUAC 2611 AD-40057.1, AD-40051.1, AD- 40075.1, AD-40046.1,AD-40040.1, AD- 40081.1, AD-40063.1, AD-40069.1 UAGACACAAAAC 2612GUUUUGUGUCUA 2613 AD-40057.1, AD-40075.1, AD- 40052.1, AD-40046.1,AD-40040.1, AD- 40081.1, AD-40063.1, AD-40069.1 AGACACAAAACA 2614UGUUUUGUGUCU 2615 AD-40058.1, AD-40075.1, AD- 40052.1, AD-40046.1,AD-40040.1, AD- 40081.1, AD-40063.1, AD-40069.1 GACACAAAACAG 2616CUGUUUUGUGUC 2617 AD-40058.1, AD-40075.1, AD- 40052.1, AD-40046.1,AD-40040.1, AD- 40081.1, AD-40064.1, AD-40069.1 ACACAAAACAGG 2618CCUGUUUUGUGU 2619 AD-40070.1, AD-40058.1, AD- 40075.1, AD-40052.1,AD-40046.1, AD- 40040.1, AD-40081.1, AD-40064.1 CACAAAACAGGC 2620GCCUGUUUUGUG 2621 AD-40070.1, AD-40058.1, AD- 40052.1, AD-40046.1,AD-40076.1, AD- 40040.1, AD-40081.1, AD-40064.1 ACAAAACAGGCU 2622AGCCUGUUUUGU 2623 AD-40070.1, AD-40058.1, AD- 40052.1, AD-40046.1,AD-40076.1, AD- 40040.1, AD-40082.1, AD-40064.1 CAAAACAGGCUC 2624GAGCCUGUUUUG 2625 AD-40070.1, AD-40058.1, AD- 40052.1, AD-40046.1,AD-40076.1, AD- 40041.1, AD-40082.1, AD-40064.1 AAAACAGGCUCA 2626UGAGCCUGUUUU 2627 AD-40070.1, AD-40058.1, AD- 40052.1, AD-40076.1,AD-40041.1, AD- 40082.1, AD-40064.1, AD-40047.1 AAACAGGCUCAG 2628CUGAGCCUGUUU 2629 AD-40070.1, AD-40058.1, AD- 40076.1, AD-40041.1,AD-40082.1, AD- 40053.1, AD-40064.1, AD-40047.1 AACAGGCUCAGG 2630CCUGAGCCUGUU 2631 AD-40059.1, AD-40070.1, AD- 40076.1, AD-40041.1,AD-40082.1, AD- 40053.1, AD-40064.1, AD-40047.1 ACAGGCUCAGGA 2632UCCUGAGCCUGU 2633 AD-40059.1, AD-40070.1, AD- 40065.1, AD-40076.1,AD-40041.1, AD- 40082.1, AD-40053.1, AD-40047.1 CAGGCUCAGGAC 2634GUCCUGAGCCUG 2635 AD-40059.1, AD-40065.1, AD- 40076.1, AD-40041.1,AD-40082.1, AD- 40071.1, AD-40053.1, AD-40047.1 AGGCUCAGGACU 2636AGUCCUGAGCCU 2637 AD-40059.1, AD-40065.1, AD- 40041.1, AD-40082.1,AD-40077.1, AD- 40071.1, AD-40053.1, AD-40047.1 GGCUCAGGACUU 2638AAGUCCUGAGCC 2639 AD-40059.1, AD-40065.1, AD- 40041.1, AD-40077.1,AD-40071.1, AD- 40053.1, AD-40083.1, AD-40047.1 GCUCAGGACUUA 2640UAAGUCCUGAGC 2641 AD-40059.1, AD-40065.1, AD- 40042.1, AD-40077.1,AD-40071.1, AD- 40053.1, AD-40083.1, AD-40047.1 CUCAGGACUUAG 2642CUAAGUCCUGAG 2643 AD-40059.1, AD-40065.1, AD- 40042.1, AD-40048.1,AD-40077.1, AD- 40071.1, AD-40053.1, AD-40083.1 UCAGGACUUAGC 2644GCUAAGUCCUGA 2645 AD-40059.1, AD-40065.1, AD- 40054.1, AD-40042.1,AD-40048.1, AD- 40077.1, AD-40071.1, AD-40083.1 CAGGACUUAGCA 2646UGCUAAGUCCUG 2647 AD-40065.1, AD-40054.1, AD- 40060.1, AD-40042.1,AD-40048.1, AD- 40077.1, AD-40071.1, AD-40083.1 AGGACUUAGCAA 2648UUGCUAAGUCCU 2649 AD-40054.1, AD-40060.1, AD- 40042.1, AD-40066.1,AD-40048.1, AD- 40077.1, AD-40071.1, AD-40083.1 GGACUUAGCAAG 2650CUUGCUAAGUCC 2651 AD-40072.1, AD-40054.1, AD- 40060.1, AD-40042.1,AD-40066.1, AD- 40048.1, AD-40077.1, AD-40083.1 GACUUAGCAAGA 2652UCUUGCUAAGUC 2653 AD-40072.1, AD-40054.1, AD- 40060.1, AD-40042.1,AD-40066.1, AD- 40048.1, AD-40078.1, AD-40083.1 ACUUAGCAAGAA 2654UUCUUGCUAAGU 2655 AD-40072.1, AD-40054.1, AD- 40060.1, AD-40042.1,AD-40066.1, AD- 40048.1, AD-40084.1, AD-40078.1 CUUAGCAAGAAG 2656CUUCUUGCUAAG 2657 AD-40072.1, AD-40054.1, AD- 40060.1, AD-40066.1,AD-40043.1, AD- 40048.1, AD-40084.1, AD-40078.1 UUAGCAAGAAGU 2658ACUUCUUGCUAA 2659 AD-40072.1, AD-40054.1, AD- 40060.1, AD-40066.1,AD-40043.1, AD- 40084.1, AD-40049.1, AD-40078.1 UAGCAAGAAGUU 2660AACUUCUUGCUA 2661 AD-40072.1, AD-40060.1, AD- 40066.1, AD-40055.1,AD-40043.1, AD- 40084.1, AD-40049.1, AD-40078.1 AGCAAGAAGUUA 2662UAACUUCUUGCU 2663 AD-40072.1, AD-40066.1, AD- 40055.1, AD-40043.1,AD-40061.1, AD- 40084.1, AD-40049.1, AD-40078.1 GCAAGAAGUUAU 2664AUAACUUCUUGC 2665 AD-40072.1, AD-40055.1, AD- 40067.1, AD-40043.1,AD-40061.1, AD- 40084.1, AD-40049.1, AD-40078.1 CAAGAAGUUAUG 2666CAUAACUUCUUG 2667 AD-40055.1, AD-40067.1, AD- 40043.1, AD-40061.1,AD-40084.1, AD- 40073.1, AD-40049.1, AD-40078.1 AAGAAGUUAUGG 2668CCAUAACUUCUU 2669 AD-40055.1, AD-40067.1, AD- 40043.1, AD-40061.1,AD-40084.1, AD- 40073.1, AD-40079.1, AD-40049.1 AGAAGUUAUGGA 2670UCCAUAACUUCU 2671 AD-40085.1, AD-40055.1, AD- 40067.1, AD-40043.1,AD-40061.1, AD- 40073.1, AD-40079.1, AD-40049.1 GAAGUUAUGGAA 2672UUCCAUAACUUC 2673 AD-40085.1, AD-40044.1, AD- 40055.1, AD-40067.1,AD-40061.1, AD- 40073.1, AD-40079.1, AD-40049.1 AAGUUAUGGAAU 2674AUUCCAUAACUU 2675 AD-40085.1, AD-40044.1, AD- 40055.1, AD-40067.1,AD-40061.1, AD- 40050.1, AD-40073.1, AD-40079.1 AGUUAUGGAAUU 2676AAUUCCAUAACU 2677 AD-40085.1, AD-40044.1, AD- 40067.1, AD-40056.1,AD-40061.1, AD- 40050.1, AD-40073.1, AD-40079.1 GUUAUGGAAUUC 2678GAAUUCCAUAAC 2679 AD-40062.1, AD-40085.1, AD- 40044.1, AD-40067.1,AD-40056.1, AD- 40050.1, AD-40073.1, AD-40079.1 UUAUGGAAUUCC 2680GGAAUUCCAUAA 2681 AD-40068.1, AD-40062.1, AD- 40085.1, AD-40044.1,AD-40056.1, AD- 40050.1, AD-40073.1, AD-40079.1 UAUGGAAUUCCU 2682AGGAAUUCCAUA 2683 AD-40074.1, AD-40068.1, AD- 40062.1, AD-40085.1,AD-40044.1, AD- 40056.1, AD-40050.1, AD-40079.1 AUGGAAUUCCUU 2684AAGGAAUUCCAU 2685 AD-40080.1, AD-40074.1, AD- 40068.1, AD-40062.1,AD-40085.1, AD- 40044.1, AD-40056.1, AD-40050.1 UGGAAUUCCUUU 2686AAAGGAAUUCCA 2687 AD-40080.1, AD-40074.1, AD- 40068.1, AD-40062.1,AD-40044.1, AD- 40056.1, AD-40050.1 GGAAUUCCUUUU 2688 AAAAGGAAUUCC 2689AD-40080.1, AD-40074.1, AD- 40068.1, AD-40062.1, AD-40056.1, AD-40050.1, AD-38131.1 GAAUUCCUUUUA 2690 UAAAAGGAAUUC 2691 AD-40080.1,AD-40074.1, AD- 40068.1, AD-40062.1, AD-38137.1, AD- 40056.1, AD-38131.1AAUUCCUUUUAU 2692 AUAAAAGGAAUU 2693 AD-40080.1, AD-38143.1, AD- 40074.1,AD-40068.1, AD-40062.1, AD- 38137.1, AD-38131.1 AUUCCUUUUAUU 2694AAUAAAAGGAAU 2695 AD-40080.1, AD-38149.1, AD- 38143.1, AD-40074.1,AD-40068.1, AD- 38137.1, AD-38131.1 UUCCUUUUAUUG 2696 CAAUAAAAGGAA 2697AD-40080.1, AD-38149.1, AD- 38143.1, AD-40074.1, AD-38137.1, AD-38155.1, AD-38131.1 UCCUUUUAUUGA 2698 UCAAUAAAAGGA 2699 AD-40080.1,AD-38149.1, AD- 38143.1, AD-38137.1, AD-38161.1, AD- 38155.1, AD-38131.1CCUUUUAUUGAA 2700 UUCAAUAAAAGG 2701 AD-38149.1, AD-38143.1, AD- 38137.1,AD-38161.1, AD-38167.1, AD- 38155.1, AD-38131.1 CUUUUAUUGAAA 2702UUUCAAUAAAAG 2703 AD-38149.1, AD-38143.1, AD- 38137.1, AD-38161.1,AD-38173.1, AD- 38167.1, AD-38155.1, AD-38131.1 UUUUAUUGAAAC 2704GUUUCAAUAAAA 2705 AD-38149.1, AD-38143.1, AD- 38132.1, AD-38137.1,AD-38161.1, AD- 38173.1, AD-38167.1, AD-38155.1 UUUAUUGAAACA 2706UGUUUCAAUAAA 2707 AD-38149.1, AD-38143.1, AD- 38132.1, AD-38161.1,AD-38173.1, AD- 38138.1, AD-38167.1, AD-38155.1 UUAUUGAAACAU 2708AUGUUUCAAUAA 2709 AD-38149.1, AD-38132.1, AD- 38161.1, AD-38173.1,AD-38138.1, AD- 38167.1, AD-38155.1, AD-38144.1 UAUUGAAACAUC 2710GAUGUUUCAAUA 2711 AD-38132.1, AD-38161.1, AD- 38173.1, AD-38138.1,AD-38167.1, AD- 38155.1, AD-38150.1, AD-38144.1 AUUGAAACAUCA 2712UGAUGUUUCAAU 2713 AD-38132.1, AD-38156.1, AD- 38161.1, AD-38173.1,AD-38138.1, AD- 38167.1, AD-38150.1, AD-38144.1 UUGAAACAUCAG 2714CUGAUGUUUCAA 2715 AD-38132.1, AD-38162.1, AD- 38156.1, AD-38173.1,AD-38138.1, AD- 38167.1, AD-38150.1, AD-38144.1 UGAAACAUCAGC 2716GCUGAUGUUUCA 2717 AD-38132.1, AD-38162.1, AD- 38156.1, AD-38168.1,AD-38173.1, AD- 38138.1, AD-38150.1, AD-38144.1 GAAACAUCAGCA 2718UGCUGAUGUUUC 2719 AD-38174.1, AD-38132.1, AD- 38162.1, AD-38156.1,AD-38168.1, AD- 38138.1, AD-38150.1, AD-38144.1 AAACAUCAGCAA 2720UUGCUGAUGUUU 2721 AD-38174.1, AD-38162.1, AD- 35667.1, AD-38156.1,AD-38168.1, AD- 38138.1, AD-38150.1, AD-38144.1 AACAUCAGCAAA 2722UUUGCUGAUGUU 2723 AD-38174.1, AD-35673.1, AD- 38162.1, AD-35667.1,AD-38156.1, AD- 38168.1, AD-38150.1, AD-38144.1 ACAUCAGCAAAG 2724CUUUGCUGAUGU 2725 AD-38174.1, AD-35673.1, AD- 38162.1, AD-35667.1,AD-35679.1, AD- 38156.1, AD-38168.1, AD-38150.1 CAUCAGCAAAGA 2726UCUUUGCUGAUG 2727 AD-35685.1, AD-38174.1, AD- 35673.1, AD-38162.1,AD-35667.1, AD- 35679.1, AD-38156.1, AD-38168.1 AUCAGCAAAGAC 2728GUCUUUGCUGAU 2729 AD-35685.1, AD-38174.1, AD- 35673.1, AD-38162.1,AD-35667.1, AD- 35679.1, AD-38168.1, AD-35691.1 UCAGCAAAGACA 2730UGUCUUUGCUGA 2731 AD-35685.1, AD-38174.1, AD- 35673.1, AD-35667.1,AD-35679.1, AD- 38168.1, AD-35691.1 CAGCAAAGACAA 2732 UUGUCUUUGCUG 2733AD-35685.1, AD-38174.1, AD- 35673.1, AD-35667.1, AD-35679.1, AD- 35691.1AGCAAAGACAAG 2734 CUUGUCUUUGCU 2735 AD-35685.1, AD-35673.1, AD- 35667.1,AD-35679.1, AD-35691.1 GCAAAGACAAGA 2736 UCUUGUCUUUGC 2737 AD-35685.1,AD-35673.1, AD- 35679.1, AD-35691.1 CAAAGACAAGAC 2738 GUCUUGUCUUUG 2739AD-35685.1, AD-35679.1, AD-35691.1 AAAGACAAGACA 2740 UGUCUUGUCUUU 2741AD-35685.1, AD-35691.1

The position (“Pos”) in NM_U00336.2 is indicated. 12 exemplary nt of theoverlap in the sense and anti-sense strand are presented; in many cases,the overlap is actually longer.

Example 3 Efficacy of KRAS RNAi Agents

KRAS RNAi agents were tested for efficacy, and the results are shown inTables 5 and 6, below.

In Vitro Screening:

Cell Culture and Transfections:

RKO cells (ATCC, Manassas, Va.) are grown to near confluence at 37° C.in an atmosphere of 5% CO₂ in McCoy's Medium (ATCC) supplemented with10% FBS, streptomycin, and glutamine (ATCC) before being released fromthe plate by trypsinization. Transfection is carried out by adding 14.8μl of Opti-MEM plus 0.2 μl of Lipofectamine RNAiMax per well(Invitrogen, Carlsbad, Calif., cat #13778-150) to 5 μl of siRNA duplexesper well into a 96-well plate and incubated at room temperature for 15minutes. 80 μl of complete growth media without antibiotic containing˜2×10⁴ RKO cells are then added to the siRNA mixture. Cells areincubated for either 24 hours prior to RNA purification. Single doseexperiments are performed at 10 nM and in some cases 0.1 nM final duplexconcentration and dose response experiments are done at 10, 1, 0.5, 0.1,0.05, 0.01, 0.005, 0.001, 0.0005, 0.0001, 0.00005, 0.00001 nM finalduplex concentration.

Total RNA Isolation Using DYNABEADS mRNA Isolation Kit (Invitrogen, Part#: 610-12):

Cells are harvested and lysed in 150 μl of Lysis/Binding Buffer thenmixed for 5 minute at 850 rpm using an Eppendorf Thermomixer (the mixingspeed is the same throughout the process). Ten microliters of magneticbeads and 80 μl Lysis/Binding Buffer mixture are added to a round bottomplate and mixed for 1 minute. Magnetic beads are captured using magneticstand and the supernatant is removed without disturbing the beads. Afterremoving supernatant, the lysed cells are added to the remaining beadsand mixed for 5 minutes. After removing supernatant, magnetic beads arewashed 2 times with 150 μl Wash Buffer A and mixed for 1 minute. Beadsare capture again and supernatant removed. Beads are then washed with150 μl Wash Buffer B, captured and supernatant is removed. Beads arenext washed with 150 μl Elution Buffer, captured and supernatantremoved. Beads are allowed to dry for 2 minutes. After drying, 50 μl ofElution Buffer is added and mixed for 5 minutes at 70° C. Beads arecaptured on magnet for 5 minutes. 40 μl of supernatant is removed andadded to another 96 well plate.

cDNA Synthesis Using ABI High Capacity cDNA Reverse Transcription Kit(Applied Biosystems, Foster City, Calif., Cat #4368813):

A master mix of 2 μl 10× Buffer, 0.8 μl 25×dNTPs, 2 μl Random primers, 1μl Reverse Transcriptase, 1 μl RNase inhibitor and 3.2 μl of H₂O perreaction are added into 10 μl total RNA. cDNA is generated using aBio-Rad C-1000 or S-1000 thermal cycler (Hercules, Calif.) through thefollowing steps: 25° C. 10 min, 37° C. 120 min, 85° C. 5 sec, 4° C.hold.

Real Time PCR:

2 μl of cDNA are added to a master mix containing 1 μl 18S TagMan Probe(Applied Biosystems Cat #4319413E), 1 μl KRAS TagMan probe (AppliedBiosystems cat # HS00180035_m1, HS00932330_m1, or HS00610483) and 10 μlTagMan Universal PCR Master Mix (Applied Biosystems Cat #4324018) perwell in a MicroAmp Optical 96 well plate (Applied Biosystems cat#4326659). Real time PCR is done in an ABI 7900HT Real Time PCR system(Applied Biosystems) using the LLCt(RQ) assay. Each duplex is tested intwo independent transfections and each transfection is assayed induplicate, unless otherwise noted in the summary tables.

Real time data are analyzed using the ΔΔCt method and normalized toassays performed with cells transfected with 10 nM AD-1955 to calculaterelative fold change.

TABLE 5 KRAS RNAi agents, 0.1 and 10 nM KD at 24 hrs 10 nM .1 nM KRASKRAS 10 nM .1 nM 10 nM .1 nM Duplex ID bio1 bio2 bio1 bio2 SD SD AVG AVGAD-35613.4 0.332 0.542 1.814 1.365 0.1484 0.3177 0.437 1.589 AD-35572.40.403 0.666 1.850 1.571 0.1859 0.1975 0.535 1.711 AD-35578.4 0.194 0.9050.622 0.485 0.5030 0.0965 0.550 0.554 AD-35584.4 0.171 0.239 0.953 0.6540.0480 0.2115 0.205 0.803 AD-35590.4 0.167 0.296 0.988 0.832 0.09190.1105 0.231 0.910 AD-35596.4 0.782 0.837 1.540 1.263 0.0392 0.19620.809 1.402 AD-35602.4 1.013 0.915 1.264 0.934 0.0694 0.2334 0.964 1.099AD-35608.4 0.818 0.631 1.120 1.093 0.1321 0.0191 0.725 1.106 AD-35614.40.898 1.025 1.929 1.195 0.0898 0.5194 0.961 1.562 AD-35573.4 0.920 0.8091.412 0.957 0.0785 0.3219 0.865 1.185 AD-35579.4 0.794 0.946 1.694 1.2440.1072 0.3189 0.870 1.469 AD-35585.4 0.861 0.738 3.016 2.552 0.08700.3281 0.800 2.784 AD-35591.4 0.458 0.325 1.238 1.073 0.0938 0.11620.392 1.156 AD-35597.4 0.948 0.897 1.523 0.864 0.0358 0.4657 0.922 1.194AD-35603.4 0.401 0.405 0.817 0.618 0.0025 0.1402 0.403 0.718 AD-35609.40.168 0.165 0.503 0.320 0.0022 0.1295 0.167 0.411 AD-35615.4 0.555 0.6201.397 0.818 0.0460 0.4099 0.587 1.108 AD-35574.4 0.762 0.650 1.009 0.6430.0790 0.2590 0.706 0.826 AD-35580.1 0.436 0.398 1.334 0.768 0.02750.4003 0.417 1.051 AD-35586.4 0.242 0.266 0.908 0.577 0.0175 0.23370.254 0.743 AD-35592.4 0.212 0.166 0.600 0.504 0.0324 0.0685 0.189 0.552AD-35598.4 0.828 0.893 1.318 1.147 0.0461 0.1205 0.861 1.232 AD-35604.40.070 0.179 0.594 0.496 0.0770 0.0692 0.124 0.545 AD-35610.4 0.415 0.6331.068 0.887 0.1537 0.1275 0.524 0.977 AD-35616.4 0.159 0.342 0.300 0.2130.1288 0.0610 0.251 0.256 AD-35575.4 0.470 0.689 0.789 0.749 0.15470.0284 0.579 0.769 AD-35581.4 0.137 0.288 0.220 0.196 0.1064 0.01700.212 0.208 AD-35587.4 0.637 0.670 1.059 0.975 0.0231 0.0591 0.653 1.017AD-35593.4 0.200 0.463 0.724 0.489 0.1859 0.1661 0.332 0.607 AD-35599.40.685 1.281 1.273 0.952 0.4217 0.2266 0.983 1.113 AD-35605.4 0.564 0.7981.423 0.897 0.1649 0.3718 0.681 1.160 AD-35611.4 0.644 0.844 1.189 0.9220.1418 0.1887 0.744 1.055 AD-35617.4 0.219 0.213 0.594 0.625 0.00470.0220 0.216 0.609 AD-35576.4 0.451 0.365 1.167 0.928 0.0604 0.16930.408 1.047 AD-35588.4 0.185 0.290 0.442 0.323 0.0736 0.0841 0.237 0.383AD-35667.1 0.497 0.623 1.030 0.857 0.0897 0.1228 0.560 0.943 AD-35673.10.367 0.405 0.771 0.693 0.0268 0.0547 0.386 0.732 AD-35679.1 0.217 0.3300.329 0.293 0.0798 0.0258 0.274 0.311 AD-35685.1 0.310 0.255 0.345 0.3390.0390 0.0045 0.283 0.342 AD-35691.1 0.258 0.257 0.955 0.535 0.00050.2968 0.258 0.745 AD-35557.1 0.843 0.624 1.056 0.947 0.1547 0.07660.734 1.002 AD-35618.1 0.447 0.425 0.611 0.439 0.0157 0.1218 0.436 0.525AD-35569.1 0.319 0.404 0.805 0.715 0.0605 0.0636 0.362 0.760 AD-35534.10.578 0.582 0.877 0.944 0.0028 0.0475 0.580 0.910 AD-35582.1 0.518 0.9740.982 0.977 0.3223 0.0035 0.746 0.980 AD-35594.1 0.441 0.317 0.884 0.6790.0877 0.1451 0.379 0.782 AD-35600.1 0.207 0.394 0.309 0.233 0.13220.0539 0.301 0.271 AD-35606.1 0.285 0.177 0.384 0.346 0.0770 0.02720.231 0.365 AD-35612.1 1.070 0.947 1.027 0.827 0.0870 0.1415 1.009 0.927AD-38127.1 0.217 0.162 0.594 0.491 0.0388 0.0728 0.189 0.542 AD-38128.10.157 0.146 0.521 0.366 0.0072 0.1095 0.151 0.443 AD-38164.1 1.112 1.9931.213 0.982 0.6224 0.1633 1.553 1.097 AD-38165.1 0.619 0.731 1.002 0.8370.0790 0.1173 0.675 0.920 AD-38160.1 1.159 1.129 1.300 0.920 0.02160.2685 1.144 1.110 AD-38161.1 0.144 0.125 0.355 0.319 0.0130 0.02560.134 0.337 AD-38133.1 0.164 0.142 0.574 0.590 0.0154 0.0113 0.153 0.582AD-38170.1 0.147 0.191 0.734 0.487 0.0311 0.1744 0.169 0.611 AD-38171.10.858 1.067 1.408 1.101 0.1480 0.2168 0.962 1.254 AD-38166.1 0.319 0.4860.846 0.848 0.1184 0.0016 0.402 0.847 AD-38167.1 0.119 0.182 0.740 0.5460.0440 0.1368 0.150 0.643 AD-38139.1 0.148 0.085 0.259 0.198 0.04450.0433 0.116 0.229 AD-38134.1 0.117 0.190 0.248 0.380 0.0514 0.09360.154 0.314 AD-38129.1 0.776 0.860 1.038 1.089 0.0596 0.0356 0.818 1.064AD-38130.1 0.528 0.820 0.900 0.846 0.2064 0.0386 0.674 0.873 AD-38172.10.076 0.094 0.289 0.247 0.0127 0.0298 0.085 0.268 AD-38145.1 0.150 0.1280.440 0.371 0.0154 0.0488 0.139 0.406 AD-38135.1 0.959 1.429 0.965 0.9000.3321 0.0459 1.194 0.932 AD-38131.1 0.135 0.173 0.414 0.279 0.02670.0955 0.154 0.347 AD-38173.1 0.609 0.988 1.132 1.373 0.2681 0.17070.798 1.253 AD-38151.1 0.211 0.181 0.378 0.554 0.0218 0.1246 0.196 0.466AD-38140.1 0.652 0.794 1.087 1.045 0.1004 0.0298 0.723 1.066 AD-38141.10.450 0.512 1.002 0.840 0.0433 0.1147 0.481 0.921 AD-38136.1 0.053 0.0960.150 0.121 0.0301 0.0199 0.074 0.136 AD-38137.1 0.283 0.259 0.677 0.5800.0169 0.0687 0.271 0.628 AD-38132.1 0.256 0.333 0.669 0.726 0.05430.0404 0.294 0.697 AD-38157.1 0.760 0.543 0.768 0.900 0.1536 0.09370.651 0.834 AD-38146.1 0.249 0.240 0.617 0.584 0.0065 0.0237 0.245 0.600AD-38147.1 0.271 0.361 0.858 0.909 0.0638 0.0365 0.316 0.883 AD-38142.10.389 0.634 0.971 0.712 0.1732 0.1831 0.512 0.841 AD-38143.1 0.378 0.6570.920 0.808 0.1966 0.0791 0.518 0.864 AD-38163.1 0.088 0.083 0.143 0.1720.0036 0.0206 0.085 0.158 AD-38152.1 0.755 0.580 1.057 0.897 0.12380.1134 0.667 0.977 AD-38153.1 0.727 0.781 0.855 1.006 0.0380 0.10670.754 0.930 AD-38148.1 0.553 0.522 0.784 0.831 0.0215 0.0333 0.537 0.807AD-38149.1 0.269 0.295 0.607 0.641 0.0186 0.0242 0.282 0.624 AD-38138.10.330 0.417 0.402 0.448 0.0615 0.0321 0.373 0.425 AD-38169.1 0.380 0.2480.626 0.540 0.0929 0.0607 0.314 0.583 AD-38158.1 0.699 0.611 0.800 1.2500.0619 0.3184 0.655 1.025 AD-38159.1 0.161 0.122 0.210 0.227 0.02740.0123 0.142 0.219 AD-38154.1 0.212 0.172 0.628 0.507 0.0286 0.08580.192 0.567 AD-38155.1 0.198 0.215 0.331 0.309 0.0122 0.0153 0.207 0.320AD-39683.1 0.471 0.536 1.135 0.812 0.0461 0.2283 0.504 0.973 AD-39689.10.630 0.627 1.148 0.979 0.0025 0.1194 0.629 1.064 AD-39695.1 0.659 0.5571.222 1.022 0.0723 0.1414 0.608 1.122 AD-39701.1 1.218 1.231 0.704 0.7240.0092 0.0141 1.225 0.714 AD-39707.1 0.384 0.160 1.387 1.087 0.15840.2121 0.272 1.237 AD-39713.1 1.157 0.481 1.128 1.228 0.4778 0.07070.819 1.178 AD-39719.1 0.885 0.631 1.178 1.189 0.1791 0.0073 0.758 1.183AD-39725.1 1.105 1.074 1.203 1.751 0.0222 0.3878 1.089 1.477 AD-39684.10.321 0.186 0.954 1.222 0.0952 0.1895 0.253 1.088 AD-39690.1 0.825 0.8280.832 0.852 0.0019 0.0139 0.826 0.842 AD-39696.1 1.071 0.996 1.087 0.8830.0532 0.1443 1.034 0.985 AD-39702.1 0.360 0.334 1.050 1.285 0.01790.1660 0.347 1.167 AD-39708.1 0.757 0.969 1.049 1.091 0.1494 0.02990.863 1.070 AD-39714.1 0.953 1.056 0.779 0.639 0.0731 0.0995 1.004 0.709AD-39720.1 0.210 0.182 0.404 0.691 0.0199 0.2030 0.196 0.548 AD-39726.10.774 0.968 0.921 1.068 0.1372 0.1037 0.871 0.995 AD-39685.1 1.022 1.3581.053 0.997 0.2378 0.0399 1.190 1.025 AD-39691.1 0.494 0.380 0.913 0.9670.0806 0.0379 0.437 0.940 AD-39697.1 0.892 1.333 0.937 1.344 0.31250.2883 1.113 1.140 AD-39703.1 1.071 1.141 0.983 0.864 0.0497 0.08421.106 0.924 AD-39709.1 0.905 1.086 0.944 1.079 0.1284 0.0953 0.995 1.011AD-39715.1 0.347 0.385 1.398 1.013 0.0265 0.2722 0.366 1.205 AD-39721.10.911 0.781 1.128 1.119 0.0918 0.0066 0.846 1.123 AD-39727.1 0.267 0.2710.911 1.038 0.0028 0.0894 0.269 0.975 AD-39686.1 0.897 0.490 0.781 0.6330.2877 0.1044 0.694 0.707 AD-39692.1 0.936 0.879 0.814 0.802 0.04030.0083 0.908 0.808 AD-39698.1 1.257 1.375 0.829 0.876 0.0834 0.03331.316 0.853 AD-39704.1 1.211 1.189 0.909 0.735 0.0155 0.1234 1.200 0.822AD-39710.1 1.389 1.136 0.881 0.862 0.1789 0.0130 1.263 0.871 AD-39716.10.787 0.943 0.991 0.963 0.1099 0.0199 0.865 0.977 AD-39722.1 1.147 1.0490.872 0.716 0.0688 0.1108 1.098 0.794 AD-39728.1 0.846 0.974 0.891 0.9280.0902 0.0264 0.910 0.909 AD-39683.1 0.374 0.307 0.996 0.982 0.04690.0098 0.341 0.989 AD-39687.1 1.015 0.775 1.035 1.642 0.1695 0.42960.895 1.338 AD-39689.1 0.340 0.328 0.769 0.762 0.0090 0.0047 0.334 0.765AD-39693.1 1.262 0.832 0.855 0.967 0.3040 0.0791 1.047 0.911 AD-39699.11.173 1.113 1.113 1.307 0.0423 0.1375 1.143 1.210 AD-39705.1 0.622 0.5820.730 0.807 0.0282 0.0542 0.602 0.768 AD-39711.1 1.996 0.864 0.720 0.8290.8006 0.0770 1.430 0.774 AD-39717.1 0.551 0.523 1.136 1.064 0.01970.0511 0.537 1.100 AD-39723.1 1.179 0.695 0.877 0.873 0.3428 0.00250.937 0.875 AD-39729.1 1.083 0.864 0.898 0.873 0.1547 0.0178 0.973 0.885AD-39688.1 0.341 0.492 0.700 0.782 0.1064 0.0577 0.416 0.741 AD-39694.10.230 0.327 0.923 1.087 0.0685 0.1164 0.279 1.005 AD-39700.1 0.529 0.7600.600 0.671 0.1631 0.0497 0.645 0.635 AD-39706.1 0.180 0.217 0.447 0.5220.0263 0.0528 0.198 0.484 AD-39712.1 0.330 0.394 0.798 0.777 0.04520.0147 0.362 0.787 AD-39718.1 0.672 0.798 0.688 0.724 0.0889 0.02550.735 0.706 AD-39724.1 0.599 1.136 0.643 0.680 0.3804 0.0261 0.868 0.661AD-39730.1 0.996 1.459 0.848 0.784 0.3271 0.0448 1.228 0.816 AD-39736.11.085 1.121 0.733 0.883 0.0254 0.1064 1.103 0.808 AD-39742.1 0.518 0.5610.651 0.703 0.0308 0.0374 0.539 0.677 AD-39748.1 0.445 0.609 0.772 0.7880.1163 0.0113 0.527 0.780 AD-39754.1 0.549 0.823 0.691 0.894 0.19420.1438 0.686 0.793 AD-39760.1 0.233 0.210 0.417 0.747 0.0158 0.23320.221 0.582 AD-39766.1 0.700 0.882 0.849 0.836 0.1291 0.0095 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1.2391.000 1.033 0.2194 0.0239 1.084 1.016 AD-39774.1 0.391 0.447 1.087 1.0870.0399 0.0003 0.419 1.087 AD-39733.1 0.605 0.569 1.020 1.212 0.02510.1355 0.587 1.116 AD-39739.1 0.950 1.271 0.959 1.030 0.2265 0.05011.111 0.994 AD-39701.1 0.798 1.193 1.221 1.018 0.2794 0.1437 0.996 1.120AD-39745.1 0.257 0.212 1.116 1.226 0.0317 0.0779 0.234 1.171 AD-39751.10.260 0.248 1.037 2.286 0.0085 0.8828 0.254 1.662 AD-39757.1 0.319 0.5661.098 0.949 0.1753 0.1053 0.443 1.023 AD-39763.1 0.235 0.300 0.667 0.5310.0463 0.0961 0.267 0.599 AD-39769.1 0.637 0.531 0.526 0.826 0.07490.2120 0.584 0.676 AD-39775.1 0.472 0.526 0.760 1.002 0.0382 0.17110.499 0.881 AD-39734.1 0.915 0.920 0.751 0.837 0.0035 0.0606 0.917 0.794AD-39740.1 0.323 0.302 0.406 0.632 0.0145 0.1593 0.312 0.519 AD-39746.10.553 0.702 0.949 1.145 0.1058 0.1382 0.627 1.047 AD-39752.1 0.440 0.5770.855 0.860 0.0965 0.0030 0.509 0.857 AD-39758.1 1.129 1.095 0.952 0.8300.0238 0.0863 1.112 0.891 AD-39764.1 1.125 0.898 1.205 1.405 0.16060.1409 1.011 1.305 AD-39770.1 0.647 0.314 0.672 0.461 0.2356 0.14860.480 0.566 AD-39776.1 1.013 0.970 1.035 0.739 0.0304 0.2092 0.992 0.887AD-39735.1 0.284 0.201 0.613 0.976 0.0588 0.2564 0.242 0.794 AD-39741.10.177 0.188 0.526 0.806 0.0074 0.1977 0.182 0.666 AD-39747.1 1.047 0.9261.247 1.483 0.0854 0.1666 0.986 1.365 AD-39753.1 1.082 0.823 1.034 1.6620.1833 0.4437 0.953 1.348 AD-39759.1 0.327 0.292 0.638 0.412 0.02520.1600 0.309 0.525 AD-39765.1 1.099 0.596 1.270 1.027 0.3554 0.17140.847 1.148 AD-39771.1 0.238 0.334 0.801 0.460 0.0679 0.2407 0.286 0.631AD-39778.1 0.217 0.250 0.502 0.354 0.0235 0.1042 0.233 0.428 AD-39784.10.698 0.598 1.036 0.944 0.0708 0.0655 0.648 0.990 AD-39790.1 0.150 0.2600.614 0.787 0.0777 0.1221 0.205 0.700 AD-39796.1 0.635 0.610 0.731 0.8460.0178 0.0813 0.622 0.788 AD-39802.1 0.349 0.150 0.898 0.970 0.14080.0509 0.249 0.934 AD-39808.1 0.734 0.972 1.079 0.955 0.1680 0.08810.853 1.017 AD-39814.1 1.070 1.294 0.979 0.968 0.1588 0.0074 1.182 0.974AD-39820.1 0.381 0.209 0.786 0.687 0.1218 0.0701 0.295 0.737 AD-39779.10.744 0.889 1.038 0.942 0.1020 0.0683 0.817 0.990 AD-39785.1 0.182 0.2180.509 0.506 0.0255 0.0022 0.200 0.507 AD-39791.1 0.214 0.308 0.556 0.5190.0667 0.0260 0.261 0.537 AD-39797.1 0.341 0.326 0.788 0.543 0.01000.1730 0.333 0.665 AD-39803.1 0.229 0.210 0.808 0.648 0.0135 0.11330.220 0.728 AD-39809.1 0.624 0.829 1.060 1.031 0.1450 0.0211 0.727 1.046AD-39815.1 0.441 0.449 0.862 0.852 0.0057 0.0072 0.445 0.857 AD-39821.10.582 0.592 0.722 0.608 0.0071 0.0806 0.587 0.665 AD-39780.1 0.748 0.7840.973 0.976 0.0252 0.0025 0.766 0.974 AD-39786.1 0.376 0.455 0.466 0.6400.0557 0.1226 0.416 0.553 AD-39792.1 1.195 1.019 0.908 1.168 0.12490.1835 1.107 1.038 AD-39798.1 0.429 0.342 0.933 0.936 0.0615 0.00200.386 0.934 AD-39804.1 0.551 0.588 0.942 0.959 0.0259 0.0119 0.570 0.950AD-39810.1 0.605 0.532 0.989 0.956 0.0518 0.0236 0.568 0.972 AD-39764.11.112 1.027 0.961 0.746 0.0602 0.1522 1.070 0.854 AD-39816.1 0.805 0.6451.014 0.839 0.1130 0.1236 0.725 0.927 AD-39770.1 0.420 0.371 0.858 0.8870.0345 0.0201 0.396 0.873 AD-39822.1 0.288 0.313 0.589 0.494 0.01780.0671 0.301 0.542 AD-39781.1 0.276 0.379 0.404 0.305 0.0725 0.07010.328 0.354 AD-39787.1 0.982 1.065 0.675 0.803 0.0584 0.0909 1.024 0.739AD-39793.1 0.165 0.291 0.487 0.488 0.0893 0.0007 0.228 0.487 AD-39799.10.444 0.540 0.686 0.746 0.0675 0.0423 0.492 0.716 AD-39805.1 0.295 0.2500.474 0.421 0.0320 0.0371 0.273 0.448 AD-39811.1 0.646 0.792 0.892 0.8820.1030 0.0070 0.719 0.887 AD-39817.1 0.583 0.824 0.848 0.846 0.17080.0012 0.703 0.847 AD-39823.1 1.229 1.075 1.080 0.859 0.1083 0.15641.152 0.970 AD-39782.1 0.605 0.757 1.162 0.883 0.1076 0.1972 0.681 1.022AD-39788.1 0.257 0.289 0.665 0.534 0.0227 0.0926 0.273 0.599 AD-39794.10.667 0.699 1.196 1.102 0.0229 0.0668 0.683 1.149 AD-39800.1 0.888 0.7341.201 0.908 0.1092 0.2072 0.811 1.054 AD-39806.1 0.505 0.637 0.630 0.8490.0935 0.1549 0.571 0.739 AD-39812.1 0.281 0.390 0.521 0.597 0.07710.0538 0.335 0.559 AD-39818.1 0.999 1.049 0.789 0.936 0.0347 0.10441.024 0.863 AD-39824.1 1.086 1.053 1.370 1.034 0.0235 0.2377 1.070 1.202AD-39783.1 0.460 0.731 0.736 0.822 0.1916 0.0609 0.595 0.779 AD-39789.10.859 1.454 1.139 1.308 0.4213 0.1195 1.157 1.224 AD-39795.1 1.165 0.9011.015 0.916 0.1866 0.0698 1.033 0.965 AD-39801.1 1.222 1.191 1.098 0.8430.0216 0.1801 1.207 0.971 AD-39807.1 0.776 0.807 1.007 1.002 0.02150.0036 0.791 1.004 AD-39813.1 0.923 1.206 1.008 0.901 0.1998 0.07531.065 0.955 AD-39819.1 0.952 1.021 1.024 0.916 0.0484 0.0765 0.986 0.970AD-39825.1 0.648 0.864 1.028 0.981 0.1529 0.0336 0.756 1.004 AD-39776.10.795 1.019 0.891 1.046 0.1581 0.1094 0.907 0.969 AD-39831.1 0.648 0.6011.018 1.034 0.0334 0.0119 0.624 1.026 AD-39837.1 0.799 0.984 0.969 0.9030.1308 0.0463 0.891 0.936 AD-39843.1 0.325 0.385 0.695 0.572 0.04270.0866 0.355 0.634 AD-39849.1 0.702 1.075 0.903 0.969 0.2638 0.04690.889 0.936 AD-39855.1 0.309 0.490 1.202 0.800 0.1280 0.2840 0.399 1.001AD-39861.1 0.762 1.162 1.020 1.000 0.2825 0.0141 0.962 1.010 AD-39867.10.873 1.162 1.219 0.918 0.2040 0.2126 1.017 1.069 AD-39826.1 1.358 1.0431.148 0.961 0.2226 0.1320 1.201 1.055 AD-39832.1 0.792 1.337 1.214 0.8730.3849 0.2413 1.065 1.043 AD-39838.1 0.429 0.270 0.793 0.530 0.11280.1859 0.349 0.661 AD-39844.1 0.572 0.789 0.833 0.692 0.1536 0.09970.680 0.762 AD-39850.1 0.535 0.231 0.505 0.529 0.2152 0.0169 0.383 0.517AD-39856.1 0.323 0.377 0.835 0.784 0.0384 0.0359 0.350 0.810 AD-39862.10.405 0.429 0.835 0.615 0.0167 0.1552 0.417 0.725 AD-39868.1 0.386 0.4840.683 0.643 0.0697 0.0284 0.435 0.663 AD-39735.1 0.168 0.255 0.439 0.2940.0616 0.1026 0.211 0.366 AD-39827.1 0.202 0.313 0.616 0.413 0.07870.1432 0.258 0.515 AD-39833.1 0.190 0.492 1.007 1.026 0.2134 0.01350.341 1.017 AD-39839.1 0.790 1.002 1.227 1.327 0.1503 0.0708 0.896 1.277AD-39845.1 0.192 0.213 0.391 0.218 0.0147 0.1220 0.202 0.304 AD-39851.10.779 0.493 1.243 0.929 0.2022 0.2220 0.636 1.086 AD-39857.1 0.602 1.4440.992 0.692 0.5960 0.2120 1.023 0.842 AD-39863.1 0.482 0.135 0.906 0.6320.2449 0.1937 0.308 0.769 AD-39869.1 0.357 0.025 0.799 0.558 0.23470.1708 0.191 0.678 AD-39828.1 1.185 1.085 1.176 0.952 0.0707 0.15851.135 1.064 AD-39834.1 1.140 1.273 1.315 1.075 0.0938 0.1698 1.207 1.195AD-39840.1 0.251 0.541 0.766 0.591 0.2050 0.1239 0.396 0.679 AD-39846.10.635 0.646 1.044 0.984 0.0077 0.0425 0.641 1.014 AD-39852.1 0.434 0.5550.707 0.719 0.0857 0.0085 0.494 0.713 AD-39858.1 0.169 0.192 0.363 0.2680.0160 0.0670 0.180 0.316 AD-39864.1 1.612 1.161 0.825 0.919 0.31890.0665 1.387 0.872 AD-39870.1 0.321 0.186 0.072 0.170 0.0952 0.06950.253 0.121 AD-39829.1 0.283 0.133 0.353 0.266 0.1060 0.0611 0.208 0.310AD-39835.1 1.265 0.792 0.460 0.641 0.3343 0.1277 1.029 0.551 AD-39841.10.345 0.267 0.416 0.369 0.0552 0.0335 0.306 0.392 AD-39853.1 0.257 0.2680.640 0.527 0.0081 0.0799 0.262 0.584 AD-39859.1 0.316 0.290 0.773 0.8860.0182 0.0801 0.303 0.830 AD-39865.1 0.228 0.216 0.456 0.424 0.00840.0231 0.222 0.440 AD-39871.1 0.218 0.338 0.502 0.571 0.0849 0.04890.278 0.537 AD-39830.1 0.284 0.293 0.770 0.716 0.0063 0.0379 0.289 0.743AD-39836.1 0.267 0.232 0.615 0.580 0.0249 0.0254 0.250 0.598 AD-39842.10.242 0.259 0.707 0.654 0.0121 0.0373 0.250 0.681 AD-39848.1 0.515 0.5911.071 1.012 0.0536 0.0416 0.553 1.042 AD-39854.1 0.853 1.128 1.035 1.0590.1943 0.0169 0.991 1.047 AD-39860.1 0.969 1.119 0.965 0.833 0.10580.0936 1.044 0.899 AD-39866.1 0.247 0.395 0.733 0.834 0.1045 0.07110.321 0.784 AD-39992.1 0.507 0.837 0.985 0.990 0.2334 0.0032 0.672 0.988AD-39998.1 0.384 0.549 0.745 0.676 0.1167 0.0486 0.466 0.711 AD-40004.10.509 0.664 1.090 1.042 0.1096 0.0340 0.587 1.066 AD-40010.1 0.212 0.2450.954 0.885 0.0232 0.0487 0.228 0.919 AD-40016.1 0.261 0.514 0.731 1.0500.1790 0.2254 0.387 0.891 AD-40022.1 0.784 1.221 0.955 0.939 0.30890.0112 1.003 0.947 AD-40028.1 0.907 1.194 1.062 0.976 0.2026 0.06081.050 1.019 AD-40034.1 0.367 0.483 0.902 0.718 0.0819 0.1298 0.425 0.810AD-39999.1 0.227 0.339 0.910 0.837 0.0789 0.0511 0.283 0.873 AD-40005.10.219 0.202 0.419 0.421 0.0121 0.0012 0.211 0.420 AD-40011.1 0.470 0.5290.731 0.637 0.0413 0.0663 0.499 0.684 AD-40017.1 0.209 0.402 0.873 0.8060.1364 0.0475 0.306 0.839 AD-40029.1 0.793 0.821 0.904 0.834 0.01990.0496 0.807 0.869 AD-39846.1 0.591 0.468 0.690 0.823 0.0867 0.09420.529 0.757 AD-40035.1 0.872 1.166 1.079 1.090 0.2083 0.0081 1.019 1.085AD-39852.1 0.439 0.346 0.784 0.995 0.0659 0.1492 0.393 0.890 AD-39994.10.396 0.517 0.936 1.097 0.0854 0.1137 0.457 1.016 AD-40000.1 0.574 0.7341.100 1.100 0.1133 0.0004 0.654 1.100 AD-40006.1 0.402 0.389 0.831 0.8000.0094 0.0223 0.395 0.815 AD-40012.1 0.211 0.435 0.704 0.929 0.15880.1593 0.323 0.816 AD-40018.1 0.692 1.163 0.808 0.933 0.3325 0.08830.928 0.871 AD-40024.1 0.182 0.428 0.772 0.716 0.1739 0.0399 0.305 0.744AD-40030.1 0.437 0.651 0.825 0.874 0.1516 0.0344 0.544 0.849 AD-40036.10.092 0.216 0.452 0.532 0.0876 0.0567 0.154 0.492 AD-39995.1 0.290 0.6860.918 0.618 0.2803 0.2122 0.488 0.768 AD-40001.1 0.672 0.758 0.709 1.0900.0607 0.2698 0.715 0.899 AD-40007.1 0.785 0.477 0.780 0.928 0.21770.1048 0.631 0.854 AD-40013.1 0.503 0.901 0.782 1.056 0.2814 0.19360.702 0.919 AD-40019.1 0.264 0.125 0.615 0.731 0.0979 0.0818 0.194 0.673AD-40025.1 0.864 1.208 0.968 1.047 0.2430 0.0562 1.036 1.007 AD-40031.10.268 0.286 0.995 0.805 0.0124 0.1344 0.277 0.900 AD-40037.1 0.579 0.6470.689 1.211 0.0484 0.3693 0.613 0.950 AD-39996.1 0.338 0.400 0.618 0.6800.0438 0.0442 0.369 0.649 AD-40002.1 0.993 0.812 0.746 0.851 0.12810.0747 0.903 0.798 AD-40008.1 0.227 0.154 0.309 0.434 0.0516 0.08790.190 0.372 AD-40014.1 0.612 0.631 0.702 0.613 0.0136 0.0630 0.622 0.658AD-40020.1 0.386 0.409 0.962 1.008 0.0164 0.0324 0.398 0.985 AD-40026.10.229 0.130 0.370 0.498 0.0702 0.0901 0.180 0.434 AD-40032.1 0.421 0.4540.979 0.954 0.0232 0.0176 0.437 0.966 AD-40038.1 0.491 0.674 0.851 1.0080.1291 0.1106 0.582 0.930 AD-39997.1 0.644 0.860 0.749 0.878 0.15310.0917 0.752 0.814 AD-39858.1 0.146 0.293 0.681 0.569 0.1043 0.07920.219 0.625 AD-40009.1 0.191 0.382 0.912 1.055 0.1351 0.1012 0.287 0.984AD-40015.1 0.897 0.856 0.778 1.065 0.0292 0.2034 0.876 0.922 AD-40021.10.225 0.282 0.850 0.658 0.0401 0.1358 0.254 0.754 AD-40027.1 0.466 1.0830.916 0.854 0.4358 0.0437 0.774 0.885 AD-40033.1 0.278 0.311 0.426 0.5880.0230 0.1150 0.295 0.507 AD-40039.1 0.257 0.447 0.666 0.739 0.13480.0511 0.352 0.703 AD-40045.1 0.263 0.147 0.526 0.945 0.0821 0.29620.205 0.735 AD-40051.1 0.162 0.126 0.665 0.837 0.0255 0.1209 0.144 0.751AD-40057.1 0.150 0.176 0.641 0.791 0.0178 0.1066 0.163 0.716 AD-40063.10.220 0.287 0.650 0.977 0.0468 0.2311 0.253 0.813 AD-40069.1 0.431 0.5590.729 0.922 0.0907 0.1363 0.495 0.825 AD-40075.1 0.399 0.613 0.834 0.9720.1511 0.0971 0.506 0.903 AD-40081.1 0.287 0.351 0.499 0.612 0.04530.0795 0.319 0.556 AD-40040.1 0.861 0.850 0.888 1.077 0.0077 0.13370.856 0.983 AD-40046.1 0.386 0.397 0.607 0.634 0.0083 0.0191 0.392 0.621AD-39864.1 0.930 0.933 0.810 1.018 0.0022 0.1468 0.931 0.914 AD-40052.10.272 0.216 0.526 0.852 0.0396 0.2299 0.244 0.689 AD-40058.1 0.398 0.3050.928 1.079 0.0655 0.1071 0.351 1.003 AD-40064.1 0.460 0.208 0.909 1.0830.1777 0.1230 0.334 0.996 AD-40070.1 0.116 0.454 0.447 0.885 0.23900.3095 0.285 0.666 AD-40076.1 0.396 1.498 0.634 1.054 0.7792 0.29690.947 0.844 AD-40082.1 0.584 0.553 0.760 1.053 0.0218 0.2073 0.569 0.906AD-40041.1 0.196 0.241 0.862 0.978 0.0322 0.0819 0.218 0.920 AD-40047.10.289 0.214 0.699 1.096 0.0535 0.2806 0.251 0.897 AD-40053.1 0.973 1.0940.717 1.079 0.0854 0.2560 1.033 0.898 AD-40059.1 1.064 0.985 0.720 1.0880.0562 0.2601 1.025 0.904 AD-40065.1 0.855 0.863 0.589 1.020 0.00570.3048 0.859 0.805 AD-40071.1 0.242 0.346 0.846 0.826 0.0739 0.01420.294 0.836 AD-40077.1 0.249 0.187 0.649 0.738 0.0437 0.0633 0.218 0.693AD-40083.1 0.286 0.339 0.807 1.130 0.0373 0.2279 0.312 0.968 AD-40042.10.549 0.288 1.205 1.288 0.1845 0.0587 0.418 1.246 AD-40048.1 0.413 0.3450.713 0.940 0.0483 0.1610 0.379 0.826 AD-40054.1 0.278 0.258 0.685 0.8250.0146 0.0989 0.268 0.755 AD-40060.1 0.288 0.230 0.781 0.811 0.04100.0217 0.259 0.796 AD-40066.1 0.779 0.829 0.950 1.284 0.0357 0.23610.804 1.117 AD-40072.1 0.273 0.169 0.579 0.963 0.0738 0.2716 0.221 0.771AD-40078.1 0.747 0.841 1.177 1.410 0.0666 0.1645 0.794 1.294 AD-40084.11.064 0.972 0.944 1.036 0.0647 0.0651 1.018 0.990 AD-40043.1 0.340 0.3130.804 0.795 0.0190 0.0065 0.327 0.800 AD-40049.1 0.179 0.159 0.339 0.3120.0141 0.0191 0.169 0.326 AD-40055.1 0.243 0.248 0.811 0.817 0.00340.0044 0.245 0.814 AD-40061.1 0.153 0.229 0.357 0.519 0.0537 0.11460.191 0.438 AD-40067.1 0.260 0.141 0.715 0.692 0.0837 0.0156 0.201 0.703AD-40073.1 0.241 0.156 0.833 0.858 0.0597 0.0180 0.199 0.846 AD-40079.10.236 0.236 0.694 0.991 0.0002 0.2099 0.236 0.842 AD-40085.1 0.188 0.2100.558 0.519 0.0155 0.0276 0.199 0.539 AD-40044.1 0.229 0.126 0.342 0.5060.0728 0.1157 0.178 0.424 AD-40050.1 1.016 0.566 0.933 1.088 0.31830.1097 0.791 1.011 AD-40056.1 0.274 0.244 0.801 1.155 0.0215 0.25060.259 0.978 AD-40062.1 0.536 0.653 0.900 1.143 0.0822 0.1719 0.595 1.022AD-40068.1 0.175 0.131 0.218 0.438 0.0313 0.1551 0.153 0.328 AD-40074.10.366 0.462 0.911 0.734 0.0674 0.1256 0.414 0.823 AD-40080.1 0.273 0.2960.844 0.932 0.0166 0.0623 0.284 0.888 AD-40071.1 0.341 0.214 0.691 0.9120.0902 0.1562 0.277 0.801 AD-40077.1 0.192 0.180 0.483 0.404 0.00830.0563 0.186 0.444 AD-40083.1 0.145 0.238 0.514 0.872 0.0657 0.25360.192 0.693 AD-40042.1 0.403 0.288 0.626 0.747 0.0814 0.0856 0.346 0.686AD-35523.3 0.228 0.350 1.165 1.104 0.0862 0.0434 0.289 1.135 AD-35529.10.367 0.368 1.099 0.831 0.0004 0.1893 0.368 0.965 AD-35535.4 0.466 0.3620.563 0.600 0.0735 0.0264 0.414 0.582 AD-35541.4 0.585 0.358 1.003 0.7130.1606 0.2052 0.472 0.858 AD-35547.4 0.491 0.546 0.732 0.626 0.03930.0753 0.518 0.679 AD-35553.4 0.785 0.690 1.043 0.744 0.0677 0.21150.738 0.893 AD-35559.4 0.387 0.437 0.779 0.776 0.0357 0.0021 0.412 0.778AD-35565.4 0.549 0.568 0.930 1.163 0.0132 0.1647 0.559 1.046 AD-35524.40.358 0.399 0.997 0.915 0.0289 0.0576 0.379 0.956 AD-35530.4 0.212 0.4061.129 0.981 0.1374 0.1046 0.309 1.055 AD-35536.4 0.463 0.272 1.028 1.1310.1352 0.0727 0.368 1.080 AD-35542.4 0.573 0.537 0.804 0.919 0.02550.0808 0.555 0.861 AD-35548.4 0.944 0.574 0.886 0.728 0.2619 0.11130.759 0.807 AD-35554.4 0.490 0.393 1.021 0.679 0.0682 0.2416 0.442 0.850AD-35560.2 1.199 0.386 0.796 0.610 0.5748 0.1310 0.793 0.703 AD-35566.41.082 0.981 0.747 0.840 0.0714 0.0652 1.031 0.794 AD-35525.2 0.645 0.7670.956 0.627 0.0864 0.2323 0.706 0.792 AD-35531.4 0.425 0.328 0.755 0.7760.0683 0.0144 0.376 0.765 AD-35537.4 0.824 0.823 0.710 0.628 0.00040.0578 0.824 0.669 AD-35543.2 0.232 0.367 0.980 0.845 0.0954 0.09490.300 0.912 AD-35549.4 1.492 0.378 1.057 0.665 0.7877 0.2769 0.935 0.861AD-35555.4 0.382 0.460 1.133 1.096 0.0554 0.0260 0.421 1.115 AD-35561.41.037 0.685 1.036 0.854 0.2488 0.1285 0.861 0.945 AD-35567.4 1.437 0.6981.098 0.909 0.5222 0.1337 1.068 1.004 AD-35526.4 1.354 0.995 0.597 0.7540.2540 0.1111 1.174 0.675 AD-35532.4 0.645 0.312 1.117 0.944 0.23570.1222 0.479 1.031 AD-35535.4 0.694 0.362 0.856 1.093 0.2353 0.16720.528 0.974 AD-35538.4 0.280 0.358 1.121 0.733 0.0551 0.2744 0.319 0.927AD-35544.4 1.562 0.806 0.895 1.104 0.5351 0.1477 1.184 1.000 AD-35550.40.988 0.683 0.745 1.159 0.2155 0.2926 0.836 0.952 AD-35556.4 0.597 0.2981.087 0.890 0.2119 0.1388 0.448 0.989 AD-35562.4 0.412 0.652 0.796 0.8570.1700 0.0436 0.532 0.826 AD-35568.4 0.324 0.544 0.986 1.171 0.15560.1304 0.434 1.079 AD-35527.4 0.218 0.272 1.079 1.097 0.0380 0.01220.245 1.088 AD-35533.4 0.488 0.226 1.236 1.089 0.1848 0.1038 0.357 1.162AD-35539.4 0.821 0.660 1.065 1.155 0.1140 0.0637 0.740 1.110 AD-35545.41.206 0.787 0.990 1.097 0.2968 0.0755 0.997 1.043 AD-35551.4 0.860 0.4041.011 1.078 0.3220 0.0473 0.632 1.044 AD-35563.4 1.183 0.977 0.908 1.2770.1461 0.2606 1.080 1.092 AD-35528.4 0.955 0.770 1.094 0.757 0.13090.2387 0.863 0.926 AD-35540.4 0.560 0.541 1.061 1.052 0.0132 0.00650.550 1.056 AD-35546.4 0.716 0.605 1.121 0.996 0.0789 0.0886 0.660 1.058AD-35541.4 0.847 0.358 1.046 1.002 0.3458 0.0314 0.603 1.024 AD-35552.40.468 0.529 1.057 1.002 0.0431 0.0391 0.499 1.029 AD-35558.4 0.424 0.3421.241 1.045 0.0578 0.1385 0.383 1.143 AD-35564.4 0.485 0.438 0.980 0.9680.0329 0.0085 0.461 0.974 AD-35570.4 0.579 0.413 0.839 1.108 0.11750.1900 0.496 0.973 AD-35571.4 0.476 0.348 0.818 0.951 0.0907 0.09430.412 0.885 AD-35577.4 0.300 0.393 0.844 0.882 0.0660 0.0267 0.347 0.863AD-35583.4 1.305 0.679 0.970 1.085 0.4424 0.0813 0.992 1.027 AD-35589.41.799 1.425 1.223 1.155 0.2646 0.0480 1.612 1.189 AD-35595.4 0.504 0.4170.976 1.013 0.0619 0.0261 0.461 0.995 AD-35601.4 0.834 0.338 1.076 0.9380.3513 0.0973 0.586 1.007 AD-35607.4 0.597 0.419 1.000 1.074 0.12560.0523 0.508 1.037 SD = standard deviation, AVG = average

TABLE 6 IC50 data: KRAS fold change values Duplex IC50_bio1 IC50_bio2AvgIC50 SD AD-39731.1 0.020 0.003 0.012 0.0122 AD-39706.1 0.004 0.0000.002 0.0028 AD-39720.1 0.012 0.002 0.007 0.0070 AD-39741.1 0.002 0.0000.001 0.0015 AD-39738.1 0.002 0.001 0.002 0.0008 AD-39870.1 0.159 0.0690.114 0.0636 AD-39845.1 0.056 0.015 0.036 0.0294 AD-39829.1 0.133 0.0270.080 0.0750 AD-39778.1 0.135 0.040 0.088 0.0670 AD-39865.1 0.179 0.0380.109 0.0996 AD-39793.1 0.003 0.078 0.041 0.0526 AD-39785.1 0.004 0.0140.009 0.0068 AD-40068.1 0.010 0.002 0.006 0.0052 AD-40008.1 0.041 0.0110.026 0.0217 AD-40026.1 0.014 0.009 0.012 0.0036 AD-40061.1 0.014 0.0040.009 0.0068 AD-40036.1 0.040 0.013 0.027 0.0196 AD-40057.1 0.030 0.1110.071 0.0577 AD-35581.4 0.017 0.027 0.022 0.0071 AD-35616.4 0.032 0.0440.038 0.0091 AD-35588.4 0.036 0.060 0.048 0.0164 AD-35604.4 0.088 0.3730.231 0.2015 AD-35592.4 0.086 0.266 0.176 0.1270 AD-35685.1 0.036 0.0190.027 0.0120 AD-38159.1 0.093 0.096 0.095 0.0027 AD-38139.1 0.092 0.3540.223 0.1849 AD-38172.1 0.130 0.180 0.155 0.0352 AD-38134.1 0.120 0.1990.159 0.0557 AD-38161.1 0.109 0.173 0.141 0.0448 AD-38131.1 0.134 0.3740.254 0.1699 AD-38128.1 0.014 0.070 0.042 0.0394 AD-38151.1 0.093 0.3150.204 0.1571 AD-38127.1 0.064 0.089 0.077 0.0177 AD-38154.1 0.041 0.2840.163 0.1721 AD-38133.1 0.036 0.203 0.120 0.1182 AD-38170.1 0.140 0.3320.236 0.1352 AD-38167.1 0.247 0.262 0.255 0.0104 AD-39735.1 0.060 0.0340.047 0.0186 AD-39858.1 0.040 0.037 0.039 0.0016 AD-39781.1 0.009 0.0160.013 0.0043 AD-39841.1 0.420 0.242 0.331 0.1255 AD-39805.1 0.057 0.0730.065 0.0114 AD-39869.1 0.182 0.142 0.162 0.0281 AD-39790.1 0.143 0.0590.101 0.0595 AD-40044.1 0.019 0.057 0.038 0.0265 AD-40049.1 0.017 0.0390.028 0.0154 AD-40005.1 0.013 0.066 0.039 0.0372 AD-40077.1 0.049 0.2410.145 0.1358 AD-40085.1 0.039 0.488 0.264 0.3173 AD-40019.1 0.103 0.3400.222 0.1677 AD-40083.1 0.108 0.426 0.267 0.2253 AD-35609.4 0.055 0.0550.055 0.0001 AD-35679.1 0.113 0.209 0.161 0.0673 AD-35600.1 0.046 0.0270.037 0.0134 AD-35606.1 0.045 0.043 0.044 0.0018 AD-38136.1 0.035 0.0430.039 0.0061 AD-38163.1 0.019 0.016 0.018 0.0017 AD-38155.1 0.236 0.2200.228 0.0118 AD-38145.1 0.111 0.230 0.171 0.0842 AD-38138.1 0.260 0.6750.468 0.2933 SD = standard deviation, Avg = average Bio1: biologicalreplicates 1 and 2; residual mRNA level relative to control.

TABLE 6.1 Efficacy of particular KRAS siRNAs. 10 nM 0.1 nM knockdownIC50 K-RAS siRNA RKO RKO MiaPaca 2 AD-35600.1 0.3 0.27 0.0934 AD-35609.40.17 0.41 0.037049 AD-38136.1 0.07 0.14 0.0346 AD-38159.1 0.14 0.220.01861 AD-38163.1 0.09 0.16 0.0383 AD-39720.1 0.2 0.55 0.005496AD-39735.1 0.21 0.37 0.0473 AD-39741.1 0.18 0.67 0.0394 AD-39760.10.0806 AD-39778.1 0.23 0.43 0.040545 AD-39822.1 1.3242 AD-39845.1 0.20.3 0.020622 AD-39870.1 0.25 0.12 0.026542 AD-40008.1 0.19 0.37 0.033536AD-40021.1 0.1217 AD-40061.1 0.19 0.44 0.009348 AD-40068.1 0.15 0.330.009477 AD-40072.1 0.2838

Various KRAS siRNAs were tested for efficacy in RKO cells in vitro.Results are provided in Table 6.1, below. Provided are the residual geneactivity at 10 nM (Column 2) and 0.1 nM (Column 3). For example, forAD-39720.1, there was a residual gene activity of 0.2, or 20%(indicating 80% gene knockdown) at 10 nM, and 0.55 or 55% (45% geneknockdown) at 0.1 nM. IC50 of knockdown in nM in MiaPaca 2 cells is alsoprovided.

TABLE 6.2 Efficacy of particular KRAS siRNAs. SEQ Guide 19mer IDProliferation Proliferation IC50 AlnyID Nicknames generic NO: BXPC3NCIH28 MiaPaca 2 AD- NA TCTCTATAATGGTG 2742 >10 >10 0.0934 35600.1 AATATAD- NA AAATACACAAAGAA 2743 >10 >10 0.037049395 35609.4 AGCCC AD- NATTTATTTCCTACTA 2744 >10 >10 0.0346 38136.1 GGACC AD- hs KRASTTTCCTACTAGGAC 2745 >10 >10 0.01861 38159.1 528 CATAG A22S26 AD- NATTTAATTTGTTCTC 2746 >10 >10 0.0383 38163.1 TATAA AD- NA AGCTCCAACTACCA2747 >10 >10 0.005495521 39720.1 CAAGT AD- hs KRAS TCAATTACTACTTG2748 >10 >10 0.0473 39735.1 321 CTTCC A22S26 AD- hs KRAS ATCAATTACTACTT2749 >10 >10 0.0394 39741.1 322 GCTTC A22S26 AD- NA ATTAGCTGTATCGT2750 >10 >10 0.0806 39760.1 CAAGG AD- NA TTCTCCATCAATTA 2751 >10 >100.040544532 39778.1 CTACT AD- NA TCGAGAATATCCAA 2752 >10 >10 1.324239822.1 GAGAC AD- NA GATTTAGTATTATT 2753 >10 >10 0.020622331 39845.1TATGG AD- NA ATATCTTCAAATGA 2754 >10 >10 0.026542015 39870.1 TTTAG AD-NA TCTAGAAGGCAAAT 2755 >10 >10 0.033536261 40008.1 CACAT AD- NATGTCTACTGTTCTA 2756 >10 >10 0.1217 40021.1 GAAGG AD- NA AATTCCATAACTTC2757 >10 >10 0.00934829 40061.1 TTGCT AD- NA AATAAAAGGAATTC 2758 >10 >100.009476662 40068.1 CATAA AD- NA ATAACTTCTTGCTA 2759 >10 >10 0.283840072.1 AGTCCTable 6.2, below, provides additional data pertaining to activity ofparticular KRAS siRNAs. The generic target sequence is provided.Proliferation was tested in vitro in MiaPaca2 cells, which are KRASmutant and are therefore K-RAS dependent. IC50 was studied, using testconcentrations from 0 to 10 nM. IC50 data are provided. For example, inthe first row, siRNA AD-39822.1 has an IC50 of 1.3242 nM.Proliferation was tested in both BXPC3 and NCIH28 cells, which are bothWild type for KRAS and are therefore KRAS independent. IC50 was studied,using test concentrations of 0 to 10 nM. In these studies, >10 nM IC50indicates that the efficacy of KRAS siRNAs was specific to KRAS (littleor no substantial off-target effects).

EQUIVALENTS

A composition of embodiment 1 is a composition comprising a RNAi agentcomprising a sense strand and an antisense strand, wherein the antisensestrand comprises at least 15 contiguous nucleotides differing by 0, 1,2, or 3 nucleotides from the antisense strand of a RNAi agent specificto KRAS provided in Table 1.

The composition of embodiment 1, wherein the composition furthercomprises a second RNAi agent to KRAS.

The composition of embodiment 1, wherein the antisense strand is 30 orfewer nucleotides in length.

The composition of embodiment 1, wherein the sense strand and theantisense strand form a duplex region 15 to 30 nucleotide pairs inlength.

The composition of embodiment 1, wherein the antisense strand and thesense strand are independently 19 to 23 nucleotides in length.

The composition of embodiment 1, wherein the RNAi agent comprises amodification that causes the RNAi agent to have increased stability in abiological sample or environment.

The composition of embodiment 1, wherein the RNAi agent comprises atleast one modified backbone and/or at least one 2′-modified nucleotide.

The composition of embodiment 1, wherein the RNAi agent comprises:

-   -   a) at least one 5′-uridine-adenine-3′ (5′-ua-3′) dinucleotide,        wherein the uridine is a 2′-modified nucleotide; and/or    -   b) at least one 5′-uridine-guanine-3′ (5′-ug-3′) dinucleotide,        wherein the 5′-uridine is a 2′-modified nucleotide; and/or    -   c) at least one 5′-cytidine-adenine-3′ (5′-ca-3′) dinucleotide,        wherein the 5′-cytidine is a 2′-modified nucleotide; and/or    -   d) at least one 5′-uridine-uridine-3′ (5′-uu-3′) dinucleotide,        wherein the 5′-uridine is a 2′-modified nucleotide.

The composition of embodiment 1, wherein the RNAi agent comprises a2′-modification selected from the group consisting of: 2′-deoxy,2′-deoxy-2′-fluoro, 2′-O-methyl, 2′-O-methoxyethyl (2′-O-MOE),2′-O-aminopropyl (2′-O-AP), 2′-O-dimethylaminoethyl (2′-O-DMAOE),2′-O-dimethylaminopropyl (2′-O-DMAP), 2′-O-dimethylaminoethyloxyethyl(2′-O-DMAEOE), and 2′-O-N-methylacetamido (2′-O-NMA).

The composition of embodiment 1, wherein the RNAi agent comprises ablunt end.

The composition of embodiment 1, wherein the RNAi agent comprises anoverhang having 1 to 4 unpaired nucleotides.

The composition of embodiment 1, wherein the RNAi agent comprises anoverhang at the 3′-end of the antisense strand of the RNAi agent.

The composition of embodiment 1, wherein the RNAi agent is ligated toone or more agent selected from: one or more diagnostic compound,reporter group, cross-linking agent, nuclease-resistance conferringmoiety, natural or unusual nucleobase, lipophilic molecule, cholesterol,lipid, lectin, steroid, uvaol, hecigenin, diosgenin, terpene,triterpene, sarsasapogenin, Friedelin, epifriedelanol-derivatizedlithocholic acid, vitamin, carbohydrate, dextran, pullulan, chitin,chitosan, synthetic carbohydrate, oligo lactate 15-mer, natural polymer,low- or medium-molecular weight polymer, inulin, cyclodextrin,hyaluronic acid, protein, protein-binding agent, integrin-targetingmolecule, polycationic, peptide, polyamine, peptide mimic, and/ortransferrin.

The composition of embodiment 1, wherein the RNAi agent is capable ofinhibiting expression of KRAS by at least about 60% at a concentrationof 10 nM in RKO cells in vitro.

The composition of embodiment 1, wherein the RNAi agent is capable ofinhibiting expression of KRAS by at least about 70% at a concentrationof 10 nM in RKO cells in vitro.

The composition of embodiment 1, wherein the RNAi agent is capable ofinhibiting expression of KRAS by at least about 80% at a concentrationof 10 nM in RKO cells in vitro.

The composition of embodiment 1, wherein the RNAi agent is capable ofinhibiting expression of KRAS by at least about 90% at a concentrationof 10 nM in RKO cells in vitro.

The composition of embodiment 1, wherein the RNAi agent has an EC50 ofno more than about 0.1 nM.

The composition of embodiment 1, wherein the RNAi agent has an EC50 ofno more than about 0.01 nM.

The composition of embodiment 1, wherein the RNAi agent has an EC50 ofno more than about 0.001 nM.

A composition of embodiment 2 comprising a RNAi agent comprising a firststrand and a second strand, wherein the first strand and second strandcomprise at least 15 contiguous nucleotides differing by 0, 1, 2, or 3nucleotides from the first and second strand, respectively, of a RNAiagent specific to KRAS provided in Table 1.

The composition of embodiment 2, wherein the composition comprises asecond RNAi agent to KRAS.

The composition of embodiment 2, wherein the second strand is 30 orfewer nucleotides in length.

The composition of embodiment 2, wherein the first strand and the secondstrand form a duplex region 15 to 30 nucleotide pairs in length.

The composition of embodiment 2, wherein the first strand and the secondstrand are independently 19 to 23 nucleotides in length.

The composition of embodiment 2, wherein the RNAi agent comprises amodification that causes the RNAi agent to have increased stability in abiological sample or environment.

The composition of embodiment 2, wherein the RNAi agent comprises aphosphorothioate and/or a 2′-modified nucleotide.

The composition of embodiment 2, wherein the RNAi agent comprises:

at least one 5′-uridine-adenine-3′ (5′-ua-3′) dinucleotide, wherein theuridine is a 2′-modified nucleotide; and/or at least one5′-uridine-guanine-3′ (5′-ug-3′) dinucleotide, wherein the 5′-uridine isa 2′-modified nucleotide;

and/or at least one 5′-cytidine-adenine-3′ (5′-ca-3′) dinucleotide,wherein the 5′-cytidine is a 2′-modified nucleotide;

and/or at least one 5′-uridine-uridine-3′ (5′-uu-3′) dinucleotide,wherein the 5′-uridine is a 2′-modified nucleotide.

The composition of embodiment 2, wherein the RNAi agent comprises one ormore 2′-modifications selected from the group consisting of:

2′-deoxy, 2′-deoxy-2′-fluoro, 2′-O-methyl, 2′-O-methoxyethyl (2′-O-MOE),2′-O-aminopropyl (2′-O-AP), 2′-O-dimethylaminoethyl (2′-O-DMAOE),2′-O-dimethylaminopropyl (2′-O-DMAP), 2′-O-dimethylaminoethyloxyethyl(2′-O-DMAEOE), and 2′-O-N-methylacetamido (2′-O-NMA).

The composition of embodiment 2, wherein the RNAi agent comprises ablunt end.

The composition of embodiment 2, wherein the RNAi agent comprises anoverhang having 1 to 4 unpaired nucleotides.

The composition of embodiment 2, wherein the RNAi agent comprises anoverhang at the 3′-end of the antisense strand.

The composition of embodiment 2, wherein the RNAi agent is ligated toone or more agents, the agent selected from a: one or more diagnosticcompound, reporter group, cross-linking agent, nuclease-resistanceconferring moiety, natural or unusual nucleobase, lipophilic molecule,cholesterol, lipid, lectin, steroid, uvaol, hecigenin, diosgenin,terpene, triterpene, sarsasapogenin, Friedelin,epifriedelanol-derivatized lithocholic acid, vitamin, carbohydrate,dextran, pullulan, chitin, chitosan, synthetic carbohydrate, oligolactate 15-mer, natural polymer, low- or medium-molecular weightpolymer, inulin, cyclodextrin, hyaluronic acid, protein, protein-bindingagent, integrin-targeting molecule, polycationic, peptide, polyamine,peptide mimic, and/or transferrin.

The composition of embodiment 2, wherein the RNAi agent is capable ofinhibiting expression of KRAS by at least about 60% at a concentrationof 10 nM in RKO cells in vitro.

The composition of embodiment 2, wherein the RNAi agent is capable ofinhibiting expression of KRAS by at least about 70% at a concentrationof 10 nM in RKO cells in vitro.

The composition of embodiment 2, wherein the RNAi agent is capable ofinhibiting expression of KRAS by at least about 80% at a concentrationof 10 nM in RKO cells in vitro.

The composition of embodiment 2, wherein the RNAi agent is capable ofinhibiting expression of KRAS by at least about 90% at a concentrationof 10 nM in RKO cells in vitro.

The composition of embodiment 2, wherein the RNAi agent has an EC50 ofno more than about 0.1 nM.

The composition of embodiment 2, wherein the RNAi agent has an EC50 ofno more than about 0.01 nM in MiaPaca2 cells.

The composition of embodiment 2, wherein the RNAi agent has an EC50 ofno more than about 0.001 nM in MiaPaca2 cells.

A method of embodiment 3 is a method comprising a method of treating aKRAS-related disease in an individual, comprising the step ofadministering to the individual a therapeutically effective amount of acomposition comprising a RNAi agent comprising a sense strand and anantisense strand, wherein the antisense strand comprises at least 15contiguous nucleotides differing by 0, 1, 2, or 3 nucleotides from theantisense strand of a RNAi agent specific to KRAS provided in Table 1.

The method of embodiment 3, wherein the KRAS-related disease is aproliferative disease, cardio-facio-cutaneous (CFC) syndrome or Noonansyndrome.

The method of embodiment 3, wherein the KRAS-related disease is aproliferative disease, cardio-facio-cutaneous (CFC) syndrome or Noonansyndrome.

The method of embodiment 3, wherein the method further comprises thestep of administering an additional treatment for a proliferativedisease, cardio-facio-cutaneous (CFC) syndrome or Noonan syndrome.

The method of embodiment 3, wherein the method further comprises thestep of administering an additional treatment for a proliferativedisease, including without limitation a solid or liquid cancer,adenocarcinoma, colorectal cancer, advanced and/or metastatic colorectalcancer, colon cancer, lung, non-small cell lung cancer and lungadenocarcinoma, acute myelogenous lung, bladder, brain, breast,cervical, endometrial, gastric, head and neck, kidney, leukemia,myelodysplastic syndrome, myeloid leukemia, liver, melanoma, ovarian,pancreatic, prostate, testicular, thyroid cancers, orcardio-facio-cutaneous (CFC) syndrome or Noonan syndrome.

The method of embodiment 3, wherein the composition comprises a secondRNAi agent to KRAS.

The method of embodiment 3, wherein the method further comprises thestep of administering an additional RNAi agent to KRAS.

The method of embodiment 3, further comprising the administration of anadditional treatment.

The method of embodiment 3, wherein the additional treatment is acomposition.

The method of embodiment 3, wherein the additional treatment is amethod.

The method of embodiment 3, wherein the additional treatment and theRNAi agent can be administered in any order.

A method of embodiment 4 is a method comprising a method of inhibitingthe expression of KRAS in an individual, comprising the step ofadministering to the individual a therapeutically effective amount of acomposition comprising a RNAi agent comprising a sense strand and anantisense strand, wherein the antisense strand comprises at least 15contiguous nucleotides differing by 0, 1, 2, or 3 nucleotides from theantisense strand of a RNAi agent specific to KRAS provided in Table 1.

The method of embodiment 4, wherein the individual is afflicted with orsusceptible to a KRAS-related disease.

The method of embodiment 4, wherein the KRAS-related disease is aproliferative disease, cardio-facio-cutaneous (CFC) syndrome or Noonansyndrome.

The method of embodiment 4, wherein the KRAS-related disease is aproliferative disease.

The method of embodiment 4, wherein the KRAS-related disease is aproliferative disease, including without limitation a solid or liquidcancer, adenocarcinoma, colorectal cancer, advanced and/or metastaticcolorectal cancer, colon cancer, lung, non-small cell lung cancer andlung adenocarcinoma, acute myelogenous lung, bladder, brain, breast,cervical, endometrial, gastric, head and neck, kidney, leukemia,myelodysplastic syndrome, myeloid leukemia, liver, melanoma, ovarian,pancreatic, prostate, testicular, thyroid cancers, orcardio-facio-cutaneous (CFC) syndrome or Noonan syndrome

The method of embodiment 4, further comprising the administration of anadditional treatment.

The method of embodiment 4, wherein the additional treatment is acomposition.

The method of embodiment 4, wherein the additional treatment is amethod.

The method of embodiment 4, wherein the additional treatment and theRNAi agent can be administered in any order.

A composition of embodiment 5 is a composition comprising a medicamentfor use in an RNAi formulation comprising a RNAi agent comprising asense strand and an antisense strand, wherein the antisense strandcomprises at least 15 contiguous nucleotides differing by 0, 1, 2, or 3nucleotides from the antisense strand of a RNAi agent specific to KRASprovided in Table 1.

Any composition above in a pharmaceutically effective formulation.

The composition according to embodiment 5, for use in a method oftreating a KRAS-related disease in an individual, the method comprisingthe step of administering to the individual a therapeutically effectiveamount of a composition according to embodiment 1.

The use of a composition according to embodiment 5, in the manufactureof a medicament for the treatment of a KRAS-related disease.

The use of a composition according to embodiment 5, in the manufactureof a medicament for the treatment of a proliferative disease, includingwithout limitation a solid or liquid cancer, adenocarcinoma, colorectalcancer, advanced and/or metastatic colorectal cancer, colon cancer,lung, non-small cell lung cancer and lung adenocarcinoma, acutemyelogenous lung, bladder, brain, breast, cervical, endometrial,gastric, head and neck, kidney, leukemia, myelodysplastic syndrome,myeloid leukemia, liver, melanoma, ovarian, pancreatic, prostate,testicular, thyroid cancers, or cardio-facio-cutaneous (CFC) syndrome orNoonan syndrome.

The use of embodiment 5, wherein the KRAS-related disease is aproliferative disease, cardio-facio-cutaneous (CFC) syndrome or Noonansyndrome.

The composition of embodiment 1, wherein all the pyrimidines are 2′O-methyl-modified nucleotides.

The composition of embodiment 1, wherein all the pyrimidines are 2′O-methyl-modified nucleotides.

Unless defined otherwise, the technical and scientific terms used hereinhave the same meaning as that usually understood by a specialistfamiliar with the field to which the disclosure belongs.

Unless indicated otherwise, all methods, steps, techniques andmanipulations that are not specifically described in detail can beperformed and have been performed in a manner known per se, as will beclear to the skilled person. Reference is for example again made to thestandard handbooks and the general background art mentioned herein andto the further references cited therein. Unless indicated otherwise,each of the references cited herein is incorporated in its entirety byreference.

Claims are non-limiting and are provided below.

Although particular embodiments and claims have been disclosed herein indetail, this has been done by way of example for purposes ofillustration only, and is not intended to be limiting with respect tothe scope of the appended claims, or the scope of subject matter ofclaims of any corresponding future application. In particular, it iscontemplated by the inventors that various substitutions, alterations,and modifications may be made to the disclosure without departing fromthe spirit and scope of the disclosure as defined by the claims. Thechoice of nucleic acid starting material, clone of interest, or librarytype is believed to be a matter of routine for a person of ordinaryskill in the art with knowledge of the embodiments described herein.Other aspects, advantages, and modifications considered to be within thescope of the following claims. Those skilled in the art will recognizeor be able to ascertain, using no more than routine experimentation,many equivalents of the specific embodiments of the disclosure describedherein. Such equivalents are intended to be encompassed by the followingclaims. Redrafting of claim scope in later filed correspondingapplications may be due to limitations by the patent laws of variouscountries and should not be interpreted as giving up subject matter ofthe claims.

1. A composition comprising a RNAi agent comprising a sense strand andan antisense strand, wherein the antisense strand comprises at least 15contiguous nucleotides differing by 0, 1, 2, or 3 nucleotides from theantisense strand of a RNAi agent specific to KRAS provided in Table 1.2. The composition of claim 1, wherein the composition further comprisesa second RNAi agent to KRAS.
 3. The composition of claim 1, wherein theRNAi agent comprises at least one modified backbone and/or at least one2′-modified nucleotide.
 4. The composition of claim 1, wherein the RNAiagent is ligated to one or more agent selected from: diagnosticcompound, reporter group, cross-linking agent, nuclease-resistanceconferring moiety, natural or unusual nucleobase, lipophilic molecule,cholesterol, lipid, lectin, steroid, uvaol, hecigenin, diosgenin,terpene, triterpene, sarsasapogenin, Friedelin,epifriedelanol-derivatized lithocholic acid, vitamin, carbohydrate,dextran, pullulan, chitin, chitosan, synthetic carbohydrate, oligolactate 15-mer, natural polymer, low- or medium-molecular weightpolymer, inulin, cyclodextrin, hyaluronic acid, protein, protein-bindingagent, integrin-targeting molecule, polycationic, peptide, polyamine,peptide mimic, and/or transferrin.
 5. (canceled)
 6. (canceled) 7.(canceled)
 8. (canceled)
 9. A method of treating a KRAS-related diseasein an individual, comprising the step of administering to the individuala therapeutically effective amount of a composition comprising a RNAiagent comprising a sense strand and an antisense strand, wherein theantisense strand comprises at least 15 contiguous nucleotides differingby 0, 1, 2, or 3 nucleotides from the antisense strand of a RNAi agentspecific to KRAS provided in Table
 1. 10. The method of claim 9, whereinthe KRAS-related disease is a proliferative disease,cardio-facio-cutaneous (CFC) syndrome or Noonan syndrome.
 11. The methodof claim 9, wherein the method further comprises the step ofadministering an additional treatment for a proliferative disease,cardio-facio-cutaneous (CFC) syndrome or Noonan syndrome.
 12. The methodof claim 11, wherein the method further comprises the step ofadministering an additional RNAi agent to KRAS.
 13. A method ofinhibiting the expression of KRAS in an individual, comprising the stepof administering to the individual a therapeutically effective amount ofa composition comprising a RNAi agent comprising a sense strand and anantisense strand, wherein the antisense strand comprises at least 15contiguous nucleotides differing by 0, 1, 2, or 3 nucleotides from theantisense strand of a RNAi agent specific to KRAS provided in Table 1.14. The method of claim 13, wherein the KRAS-related disease isaproliferative disease, cardio-facio-cutaneous (CFC) syndrome or Noonansyndrome.
 15. (canceled)
 16. (canceled)
 17. (canceled)
 18. (canceled)19. The composition of claim 1, wherein all the pyrimidines are 2′O-methyl-modified nucleotides.
 20. (canceled)
 21. The composition ofclaim 1, wherein the RNAi agent has an EC50 of no more than about 1 nMin MiaPaca2 cells.
 22. The composition of claim 1, wherein the RNAiagent is capable of inhibiting expression of KRAS by at least about 70%at a concentration of 10 nM in RKO cells in vitro.